Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof

ABSTRACT

A transdermal delivery system (TDS) for use in treatment of living bodies may be applied as an open (liquid, gel) or closed (patch) article. The TDS is composed of a particular active agent which dictates an associated selection of certain solvents, solvent modifiers, solute modifiers and skin stabilizers with which the medicament forms a true solution that rapidly crosses the skin barrier. The associated selection of the particular solvents, solvent modifiers, solute modifiers and skin stabilizers is based on a balancing of the molecular properties of all the components against the molecular properties of all the components plus the particular active agent. The TDS may also include a source of cellular energy to induce CAMP or cGMP. The TDS improves delivery of active agents having a molecular weight greater than 340 Daltons and increases dosage above 0.25 mg/day for such active agents.

RELATED APPLICATIONS

This application is a division of Ser. No. 09/381,095, filed May 11,2000, which is a sec. 371 application of PCT/US99/15297, filed Jul. 7,1999, which claims priority to Provisional Application No. 60/091,910,filed Jul. 7, 1998, now U.S. Pat. No. 6,444,234 issued Sep. 3, 2002.

FILED OF THE INVENTION

This invention relates to transdermal delivery of active agents,including pharmaceuticals, cosmetics, nutrients, and the like, acrossthe skin barrier of humans or other animals and to a method fordeveloping new transdermal delivery systems for any particular polar ornon-polar active agent of small or large molecular size, which deliverysystems are capable of rapidly delivering the active agent to a targetedlocation systemically or locally.

BACKGROUND OF THE INVENTION

The pharmaceutical industry is actively seeking to develop new andimproved modes of drug delivery to enhance the effectiveness ofparticular drugs, including, targeting the drug to the intended site,reducing dosage, decreasing toxicity, and the like. Major efforts areunderway in molecule stabilization for parenteral applications, extendedrelease modalities for enteral drugs and photactivated chemotherapeuticmolecules, for example. Delivery of medications via transdermal drugdelivery (TDD) systems (patches) has also seen dramatic developments,see U.S. Pat. Nos. 4,879,275; 3,996,934; and 3,731,683. For example, itis now generally agreed that chemical modification of the barrierproperties of the skin is a safe and effective method to enhancepenetration of medicaments (Ref. 1). However, to some extent it seemsthat this mode of delivery has reached its technological limits.

The present inventors have analyzed the TDD systems and have been ableto identify certain limiting factors. These include, for example,limitations to compounds which are

lipophilic medicaments;

medicaments with an effective therapeutic dose of less than 1 mg perday;

medicaments having a melting point below about 150° C.;

medicaments having molecular weight of from less than about 300 to about500 Daltons (the larger the molecule, the less is the amount deliverablevia the stratum corneum);

molecules which do not elicit a rapidly cascading immune response whentransmigrating the skin.

With regard to the molecular weight limitations, currently commerciallyavailable TDD systems deliver molecules with molecular weights less thanabout 340D and in amounts generally less than about 1.0 mg per 24 hours.

Additionally, candidate medicaments should also, preferably, be solublein ethanol and/or isopropanol and/or glycols or dimethyl sulfoxide(DMSO) and should not be chemically altered by solubilization. Anotherpotentially limiting factor is for compounds which can have efficacy atrelatively small doses introduced systemically via the capillary net ofthe dermis. Main limiting factors thus include molecule size andirritation potential of the medicament plus solvent(s) and othercomponents.

The inventors have also analyzed the chemistry and chemical structuresof active ingredients and carriers of transdermal delivery systems andhave found other limiting factors leading to the limited success oftransdermal drug delivery. Most typically it has been observed thatthese systems have not been widely acceptable because the drug carrierschemically bound with the medicament resulting in non-bioavailablecompounds transmigrating the skin; or/and the carrier, e.g., DMSO,reduces the medicament yielding a non-bioavailable or non-bioequivalentcompound or creates toxic by-products of transmigration.

Only about 1% or less of known medicaments would not be excluded foradministration by a TDD system based on the above limiting factors.Still further, TDD systems currently available are usually subject tobroadly varying results as a function of the circulation efficiency ofthe patient. Age, size and weight of the patient all impact howefficiently these systems perform. For most TDD systems there isvirtually no drug penetration for the first hour after application andoften 24 to 48 hours are required to achieve a therapeutic level.

The anatomy and physiology of the integument was analyzed to understandthe complex protective mechanism of physical, biochemical andbio-electrical gradients which work to minimize the penetration offoreign substances and sensitize the organism to react more rapidly andaggressively to future exposures. As a result of this analysis it ispostulated that:

The primary pathway of transdermally delivered drugs is paracellular,i.e., around the cells, then through the elastin glue.

The glue-like compound, elastin, composed of collagen and hyaluronicacid and other lipids, which occupies the interstices between the cellsof the top-most layer of the skin (i.e., the epidermis, including, e.g.,stratum corneum (SC), lucidum, granulosum, spinosus) must be dissolved(or otherwise disrupted) in order for a medicament or other activeagent, dissolved in a solvent, to transmigrate through viable skin (VS)to the subcutaneous tissues where the cutaneous plexi of the capillarynet can be reached and/or deeper penetration achieved (Ref. 2). When theelastin is dissolved, other agents may then transmigrate the outerlayers, so the body immediately begins to attempt to repair the damagecaused by the dissolution.

Skin penetration enhances (SPE) which delipidize can reduce the barriercapacity of the SC as a function of species of enhancer and itsconcentration. Permeability may often be adjusted by modifying the HLBof the enhancer (Ref. 3).

Capilary circulation acts as a sink for the medicament, thus maintaininga steep chemical potential gradient across the skin (Ref. 4).

Diffusivity of a drug molecule is dependent on properties of both themedicament and the medium (carrier). The diffusivity in liquid media, ingeneral, tends to decrease with increased molecular volume (Ref. 5).

The rate of skin penetration is a function of (1) the DiffusionCoefficient, (2) the barrier partitioning tendencies, (3) bindingaffinities, and (4) the rate of metabolism of the medicament by the skin(Ref. 6). The Diffusion Coefficient of the medicament is influenced by(1) molecular weight, (2) molecular structure, (3) additives, (4) rateof metabolism of the medicament by the skin. Diffusion is also dependenton the carrier, with diffusivity decreasing with increased molecularvolume.

An optimum HLB is required for a medicament to penetrate efficiently.The optimum HLB may be predicted by plotting the log (PermeabilityCoefficient)vs. Log (Oil and Water Partition Coefficient) of themedicament for the SC and the VS (Ref. 4).

Highly lipophilic drugs bind readily in the VS and, therefore,dissolution into the blood is minimal (Ref. 6). Therefore, highlylipophilic drugs must be shielded to inhibit such binding.

Skin metabolizes drugs effectively, so metabolism issues in the skin,such as, enzyme saturation and/or inhibition, medicament/metabolitefluxes (e.g., how rapidly and completely does the drug metabolize to adifferent form) should be taken into account.

Un-ionized species of medicaments transmigrate more readily (Ref. 4).Generally, un-ionized species are two orders of magnitude more permeablethan their ionized form.

The Hilderbrand Solubility Parameter (HSP) is useful for predicting themutual solubility and compatibility of medicaments, SPEs, and polymersand for optimizing skin permeability (Ref. 7). The HSP describes thatattractive forces between molecules and is defined as the square root ofthe Cohesive Energy Density (Ref. 8). The HSP spans a range where thelow value is associated with lipophilic compounds and a high value withhydrophilic compounds. The solubility parameter can be furtherpartitioned into polar, non-polar, dispersive, and hydrogen bondingcomponents which are useful to predict molecular interactions betweencompounds (Ref. 9). The solubility parameter or Cohesive Energy Densityis synonymous with lipophilic/hydrophilic properties (Ref. 4). Dipolemoment is also an expression of the Cohesive Energy Density.

Transient increases in cutaneous blood flows may result in increasedsystemic absorption of the drug from the depot of the TDD (Ref. 5).

Furthermore, cellular biological issues were reviewed in order toidentify and categorize membrane and organelle functions, both in theintegument and in other tissues, which might be subject to variationswhich might help or hinder tissue transmigration of a medicament andsolvent. In particular, it is proposed that,

SPE's and solvent modification systems can cause irritation apart fromthe medicament they are delivering. Chronic exposure to irritants hasthe potential to become carcinogenic and, therefore, care must be takenin the design and testing of TDD systems.

Efferent tactile corpuscles of nerves form an “early warning detectionsystem.” The cellular and humoral components of this peripheral immunesurveillance system present in the skin are responsible for the genesisof a hapten-specific, cell-mediated immune response following thepenetration of the skin by, and complexing of skin components with,sensitizing chemicals and drugs (Ref. 10). If a drug is able topenetrate the skin and covalently bind with amino acids in the skin,dermal hypersensitivity is possible. If the hapten-protein conjugate isof sufficient size to be recognized as a foreign antigen, a specificantibody or cell-mediated immune response will ensue that sensitizes theskin's immune system to the hapten molecule. Upon re-exposure of theskin to the sensitizing chemical, a dermal hypersensitivity reaction ofthe delayed onset type 4 hypersensitization may be elicited (Ref. 11).Effective transmigration must be able to elude or minimize this responseto effectuate repeated challenge without anaphylaxis or ACDsensitization. Avoiding binding in the skin is, therefore, an importantobjective.

Some SPE's reduce residence time of the medicament in the skin andreduce the extent of cutaneous metabolism thereby reducing exposure tothe medicament or metabolite. The faster the medicament moves, the lessmetabolism takes place. Rate and extent of metabolism in the liver andskin on a unit basis are virtually the same and disposition is the sameby IV dosage (Ref. 12).

Virtually any solvent used to dissolve and form a medium for drugs istoxic on the cellular level at the concentrations required, therefore,the tissues are effectively challenged with eliminating the medicamentand the solvent, thereby draining substantial energy from the system.

Most challenges force the cell to expend adenosine triphosphate (ATP) tomove compounds across gradients or to maintain barrier integrity againsttransmigration by compounds.

Adenylate cyclase substrate for the cAMP system, when varied, can yieldsubstantial changes in a cell's tolerance for, and ability to recoverfrom, the challenge of dermal transmigration, accelerating the time lineto a steady, bio-available equilibrium of the medicament (Ref. 13).

Topical, transdermal drug delivery modalities, nevertheless, havecertain apparent benefits so that there is still much activity not onlyin the patch systems but also in the non-patch transdermal deliverysystems, such as gels, ointments, and other topical formulations.

OBJECTS OF THE INVENTION

Accordingly, it is a primary object of the invention to providecompositions for the rapid transdermal administration of medicaments orother active agents to humans or other animals which does not requireuse of a “patch” delivery system.

Another object of the invention is to provide compositions effective fortransdermal delivery of active compounds not previously amenable to thisroute of administration, particularly for pharmacological agents havingmolecular weights in excess of about 300 D and/or at dosages in excessof 0.25 mg/cm² per day, especially, in excess of about 1 mg/cm²/day.

It is another object of the invention to provide topical compositionsfor transdermal delivery of active agents for humans and other animalswhich leaves the barrier properties of the skin substantially intact andwhich invokes only minimal or substantially no immune response at thesite of application.

Still another object of the invention is to provide a standardizedsolvent/carrier base system which is useful for forming topicallyapplied compositions for transdermal administration of many differentmedicaments with none or only minimal modification required to achieve atrue solution of the medicament and effective, safe, and rapidtransmigration of the medicament through intact skin.

Another object of the invention is to provide safe and effectivecompositions for transdermal administration of a variety of medicamentsand other active agents of low or high molecular weight which allowsrepetitive applications over short or long periods of time at the samesite on the intact skin without causing damage to or immunologicalreaction by the skin.

It is another object of the invention to provide a method forformulating safe and effective compositions for topical transdermalapplication of an active agent by matching the solvent/carrier systemfor the particular active agent which will allow the agent totransmigrate across the skin barrier with no or only minimalimmunological response at the site of application and without degradingthe chemical structure or bioactivity of the active agent.

These and other objects of the invention will become clearer upon reviewof the following more detailed description and specific embodiments, andwith the aid of the accompanying drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results obtained in Example13, for the flux (μg/cm²) vs. time (h), of morphine (as morphinesulfate) under open (lotion) conditions using the topical deliverysystem SDS-L;

FIG. 2 is a graphical representation similar to FIG. 1 but for testingunder closed (patch) conditions using the SDS-L delivery systemdescribed in Example 13;

FIG. 3 is a graphical representation similar to FIG. 1 but using thetopical delivery system SDS-S, as described in Example 13;

FIG. 4 is graphical representation similar to FIG. 2 (closed patchapplication) for transdermal delivery of morphine, but using the topicaldelivery system SDS-S.

SUMMARY OF THE INVENTION

Based on the above observations and reviews of the overall biologicalsystems of the skin and vascular organs, including at the cellular andmicrobiological levels, it was concluded that an effective and“universal” transdermal drug delivery system (as used herein, unless thecontext indicates otherwise, the reference to “drug” delivery isintended to include not only drugs, medicines, pharmacologicals, andother biologically active ingredients, but also other active agents,such as, cosmetically active substances, nutrient substances and thelike) should have the following characteristics and features:

ability to dissolve and emulsify the active agent down to individualmolecules (true solutions) in a carrier which remains liquid long enoughto penetrate the epidermis;

remains stable as formulated and not form an irreversible complex withother substances;

does not damage the skin with repeated use;

releases the active agent appropriately and does not alter the agent orleave as residual compounds which might be sensitizing.

The present invention provides a topical formulation for the transdermaldelivery of an active agent which addresses the design of the integumentas a biologically responsive physical, chemical and bioelectricalbarrier against the active agent(s) and solvent(s). Accordingly,solvent(s) and modifying component(s) are selected so that permanent orstrong covalent bonds with the medicament or other active agent are notformed, while the complexes that are formed facilitate movement of thecomplex past the viable skin to its optimal targeted internalcirculation system of blood, lymph or neural, or beyond these systems,wherein the complexers and modifiers are readily stripped from theactive agent at the intended site of application, thereby leaving theactive agent free to seek the appropriate receptors once released.

At the same time, the formulations according to this invention aredesigned to modify the active agent and solvent(s) to minimize theirreactivity and sensitizing characteristics as well as making the activeagent more “slippery” thereby facilitating transmigration through theskin. By facilitating the transmigration and increasing the rate ofdiffusion of the active agent and other system components through theskin the less time the formulation will have to remain in the tissuesand the lower the physiological response. In part, this is accomplishedby selecting solvent(s) and modifier(s) to provide a true solution,namely a solution of the various components in the solvent system on amolecular level, while at the same time forming a protective “coating”or temporary complex with the active agent to facilitate its intacttransmigration through the skin.

The present invention also provides transdermal drug delivery systemswhich may include a substance which can assist the skin in repairingdamage which is caused by the transmigration of the delivery system.

In one broad aspect of the invention there is provided a topicalformulation for rapid transdermal delivery of an active agent throughintact skin wherein the formulation includes (1) active agent, (2)solvent system in which the active agent is soluble, and (3) a substancecapable of in vivo stimulation of adenosine 3′,5′-cyclic monophosphate(cAMP) or cyclic guanosine 3′, 5′-monophosphate (cGMP).

The substance capable of in vivo cAMP stimulation is, preferably, anextract of Coleus Forskholi, especially a labdane diterpene, such asForskolin, or colforsin or coleonol.

The formulation may and, preferably will, also include one or moreadditional ingredients effective for enhancing percutaneous absorptionof the active agent in its intact, bioactive form. Such additionalagents include, for example, one or more of modifiers for the activeagent (solute) and/or solvents, such as, methylsulfonylmethane, terpenecompounds, skin penetration enhancers, glycerylmonolaurate, quaterniumcationic sufactants, N,N-dialkyl alkanolamines, such asN,N-diethylethanolamine, steroids, such as dehydroepiandosterone, oilysubstances, such as eicosapentanoic acid, vitamins, such as A, D₃, E,K₁.

According to a particular embodiment of the invention the topical,liquid, composition is effective for transdermal delivery of highmolecular weight active agent (solute), especially medicaments and otheractive agents having molecular weights of at least about 350 Daltons(350D), at delivery rates of greater than about 0.25 milligrams (mg) persquare centimeter (cm²) per 24 hours. According to this embodiment, thecomposition may be formulated as a unit dosage (e.g. one cubiccentimeter (1 cc) containing from about 0.25 to about 1.5 mg of activeagent having molecular weight of at least about 350D in a carrier inwhich the active agent is completely dissolved. The carrier includes asolvent system in which the active agent is at least substantiallysoluble, at least one solvent modifying compound to facilitatetransdermal delivery of the active agent and, as necessary, to increasesolubility of active agent in the solvent system; and at least onesolute (active agent) modifying compound forming a non-covalently bondedcomplex with the solute. In this embodiment, too, addition of asubstance, e.g., Forskilin, for stimulating cAMP production, orsubstance for stimulating cGMP production, is preferred for its abilityto increase the rate of percutaneous absorption of the active agent intoand through the stratum corneum (sc) and viable skin (vs).

In one particular aspect the present invention provides a topicalformulation for the transdermal delivery of an active agent having agiven polarity and dipole moment; the formulation includes:

(A) at least one solvent in which the active agent is soluble or ismodified to solubilize the active agent, and which has substantially thesame dipole moment as that of the combination of active agent plussolvent system;

(B) at least one solvent modifier having common structural features asthat of the active agent and comprising an ethylenically unsaturatedpolar group containing at least one functional group containing at leastone heteroatom selected from the group consisting of oxygen, nitrogenand sulfur;

(C) at least one metabolizable solute modifier comprising a compoundcapable of forming a temporary (non- covalently bonded) complex with theactive agent;

(D) at least one source of cellular activation energy; and, optionally,

(E) at lease one skin stabilizer for stimulating the body's repairmechanisms in response to transdermal migration of the active agentthrough the skin.

The present invention also provides, in a specific embodiment, a topicalformulation for the transdermal delivery of a medicament (or otheractive agent) having given polarity, the formulation including

(a) at least one non-aqueous non-toxic solvent selected from the groupconsisting of lower aliphatic mono- and poly-hydroxy compounds;

(b) limonene or lemon oil;

(c) methylsufonylmethane;

(d) skin stabilizer comprising at least one compound selected from thegroup consisting of aliphatic carboxylic acid having from about 8 toabout 32 carbon atoms, an ester of said aliphatic carboxylic acid withan aliphatic alcohol having from 1 to about 20 carbon atoms, whereinsaid ester has a total of from about 9 to about 36 carbon atoms, VitaminD₃ and mixtures thereof;

(e) solute modifier comprising at least one compound selected from thegroup consisting of 3,3′-thiodipropionic acid, ester thereof, saltthereof, oxindole alkaloid, polyphenolic flavonoid, sugar adduct of agluconuride, isoflavones, phosphatidyl serine, phosphatidyl choline,vitamin D₃ and Vitamin K_(1,)

(f) at least one substance which induces in situ generation of cAMP orcGMP.

In accordance with a particularly preferred embodiment of this aspect ofthe invention the component (f) is, or comprises, forskolin orColforsin, especially forskolin.

According to still another aspect of the invention there is provided amethod for forming a composition for the topical application to the skinof a human or other animal for the transdermal delivery of an activeagent of known or predetermined polarity contained in the composition.The method includes the steps of

selecting a solvent in which the active agent is at least substantiallysoluble;

selecting modifying agents for each of the solvent and active agent suchthat when the active agent is dissolved in a solvent system comprisingsolvent and modifying agent there will form a complex of at least onemodifying agent weakly associated with the active agent through van derWaals forces and/or hydrogen bond affinities; said modifying agentscomprising at least one ethylenically unsaturated compound having apolar group and an oxygen, nitrogen and/or sulfur containing functionalgroup, and at least one compound for balancing at least one molecularproperty characteristic of the solvent system and active agent, saidmolecular property characteristic being at least one of electrostaticenergy, non-bonded energy, polarisability and hydrophobic bonding, andthe polarities of the modifying agents are such that the dipole momentof the active agent closely matches the dipole moment of the activeagent plus solvent system, and

forming the pharmaceutical composition by mixing each of the activeagent, solvent and modifying agents.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The present invention provides a transdermal delivery system which isable to quickly introduce a medicament or other active agent throughintact skin or mucous membrane or other viable membrane or externalcovering of animal, including human, or plant, while minimizing damageand therefore, minimizing the immune response of the skin or membrane tothis introduction/challenge.

While the foregoing and following descriptions are given with respect totransdermal or percutaneous administration of drugs or other classes ofactive agent through human or animal skin, the principles andcompositions disclosed herein are not so limited but will also begenerally applicable to administration of a broad spectrum of activeagents, including medicines, drugs, pharmacologicals and non-bioactivesubstances or agricultural chemicals for treating plants, and otherviable animal membranes. In this regard, it will also be appreciated bythose skilled in the art that certain substances may exert medicinal orpharmacological activity when used at high concentration while at lowerconcentration and/or for a lower extent of transmigration, e.g., withoutsubstantially reaching beyond the viable skin to the vascular orcapillary network, will exert only a cosmetic effect or weakerpharmacological activity. It will also be appreciated that certaincompounds, for example, quaternary ammonium compounds, may in some casesconstitute an active ingredient while in other cases such compounds maybe included as modifying agents, skin stabilizing agent or for otherfunctional effect.

Accordingly, the term “active ingredient” or “active agent” or similarterm is intended to refer to that ingredient or ingredients in theformulation which is intended to and expected to have a half-life ofmore than a few minutes (e.g., at least about 2, preferably at leastabout 5 minutes) after introduction into the body and the onlyingredient(s) included to accomplish, in the case of a drug or othermedicinal or pharmacological agent, a therapeutic outcome,pharmaceutically, or, in the case of an agricultural agent, anequivalent therapeutic outcome, agriculturally.

Furthermore, unless the context indicates otherwise, terms such as“transdermal” or “skin” should be construed to also include penetrationthrough the outer layer of various plant forms, such as trees, floweringplants, cacti, and the like, including, for example, stems, leaves,shoots and the like.

Rapid introduction of the active agent enables:

minimal immune response or anaphylaxis, and

repetitive dosing over the same area of skin over a short term or, ifneeded, for a longer course of therapy.

In order to accomplish the above and other objectives the deliverysystem is designed to (1) create a transient modification of thoseaspects of the solvents and solutes which encounter or trigger thebody's defense mechanisms against dermal transmigration and, (2)minimize or offset any damage done by dermal transmigration.

The transient modification (1) is manifested by the formation of acomplex between the solute (active agent) and the solvent or solventsand modifying agents or modifiers for the solvent(s) and/or the solute.These complexes are formed as non-chemical true solutions of the solutein solvent wherein the components of the complex are held togetherthrough weak association, including van der Waals forces and/or hydrogenbond affinities but, substantially no covalent bonding. Furthermore, thecarrier for the solute which includes the solvent(s) and modifyingagent(s), as will be described below in further detail, is selected tohave common structural elements (e.g., physical and molecularorientation, size, shape, etc. and which may be considered as the“morphological” structure of the compound) which are similar to andcompatible with the structural elements (morphology) of the solute(active agent) and otherwise exhibits an affinity for the solute wherebythe solute is attracted to and associates with the carrier to form a3-dimensional structure which may be analogized to a Velcro-typemechanism. That is, the carriers of the transdermal delivery system ofthis invention are designed for each particular drug or other medicamentor active agent which allows the resulting complex of active agent topass through each of the different layers of the skin's defenses withminimal or no irritation while carrying the active agent in its intact,non-dissociated state. As the complex passes through each layer orlayers one or more modifying agents of the complex may be stripped awayfrom the complex, usually by preferentially bonding or reacting with acomponent or components of the skin layer, but without reacting ordisassociating the active agent. This mechanism thus allows the activeagent to reach and be absorbed by or react with its intended target,usually absorption into the vascular or capillary network.

In practice, however, in view of the overall similarities of commonstructural elements with and among large classes of medicaments, it hasbeen possible to design a standard or stock solution which, with onlyminor modifications or fine tuning, can be used for many differentactive agents.

The stock solution will generally include (A) solvent(s); modifyingagents including (B) solvent modifier(s); and (C) metabolizable solutemodifier(s); (D) source(s) of cellular activation energy; and (E) skinstabilizer(s). Other optional ingredients may also be included, forexample, (F) capillary dilator(s); (G) enzyme activator(s). The activeagent is mixed with the stock solution, further modified, as necessary,to increase solubility and/or more closely match the molecularproperties of the stock solution plus active agent to that of the activeagent, taking into account one or more effects of the molecularinteractions of molecules in a liquid. Each of these components will nowbe described in further detail.

It is understood that all ingredients used in the compositions of thisinvention must, within the applied and recommended dosages, be non-toxicand safe for human use. Also, all amounts, parts and percentages in thefollowing description and appended claims are on a weight basis unlessotherwise noted.

(A) Solvents

The solvent is the principal component of the carrier for the activeagent and, preferably, is one in which the active agent is soluble or atleast substantially soluble or can be made soluble or become moresoluble, by addition of one or more solvent modifying agents. As usedherein, by “substantially soluble” is meant that the minimum effectivedose of the active agent, generally at least about 0.25 mg, preferablyat least about 0.5 mg, especially preferably about 1 mg, or more, willdissolve in 1 cc of the solvent(s) or in 1 cc of a mixture of thesolvent(s) with solvent modifying agent(s). Suitable solvents may beselected from any of the solvents normally used for medicaments,cosmetics, nutrients or other active agent to be deliveredtransdermally.

Preferred solvents include lower alcohols of from about 2 to about 6carbon atoms, preferably from 2 to 4 carbon atoms and may bemonoalcohols, such as, for example, ethanol, isopropanol, sec-butanol,or polyols, such as, for example, ethylene glycol, propylene glycol,butylene glycol, glycerol. Mixtures of solvents may be used. Othersolvents, such as ketone, e.g., acetone, methylethyl ketone, ethers,e.g., ethylether, may also be used, in amounts which will be safe andnon-toxic in use.

While the solvent system is generally non-aqueous, water may be used forwater soluble active agents and for those drugs or other active agentswhich are stable in the presence of and not denigrated by the presenceof water. Water may also be introduced as a component of one of theother ingredients, for example, as an alchohol:water azeotrope, etc.When water is present in the solvent it will usually constitute lessthan about 50 percent, preferably less than about 10 percent,especially, preferably, less than about 2 percent, by weight of thetotal solvent although more or less may be used depending on the activeagent and so long as the objective of the invention can be met.Furthermore, as will become apparent by the examples to follow, thecompositions of this invention and utilizing the principles which willbe described in more detail, hereinafter, may also be formulated asaqueous emulsions, including wherein the aqueous emulsions, as is thecase with non-aqueous (usually less than about 5%, be rapidly absorbedby the release the active agent or agents in, typically, less than oneminute.

Generally, the total amount of solvent(s) will be selected to assuredissolution of the solute and other additives and provide suitableproduct viscosity. Generally, the amount of solvent(s) falling withinthe range of from about 5 to about 90 percent, preferably from about 25to about 75 percent, based on the total composition, may be used.

(B) Solvent Modifiers

A solvent modifier is selected to modify the polarity of the solventsystem to closely match that of the active ingredient (solute).Therefore, solvent modifiers will usually be polar compounds (from polarions in solution) and will usually contain a functional group containingoxygen, sulfur or nitrogen in its molecule. Also, if the active agent isunsaturated the solvent modifier will usually also contain double bondsin the straight-chain or cyclic portion to match the structure of theactive agent. Most importantly, the solvent modifier or mixture ofsolvent modifiers enables the solvent system (solvent(s) and solventmodifier(s)] to form a weak complex with the active agent, i.e., anassociation via van der Waals forces and/or hydrogen bonding, thusyielding a stable composition with a high solute/solvent ratio. As usedherein, “stable” is intended to have its normal and usual meaning,namely, that the composition may be stored at room or elevatedtemperature for one or more days, usually 30 or more days, withoutundergoing phase separation. By “high solute/solvent” ratio is meant atleast 0.25 mg solute per cubic centimeter or solvent (or solvent plusmodifying agents) and, more generally, often amounts of solute exceedingthe solubility of the solute in the solvent alone, or in each solvent ofa multi-solvent system.

As noted above, solvent modifiers may be individually (or as a group)selected from substances having structural elements in common with theactive agent. However, it has been found that for many bio-activecompounds and other active agents, a relatively small group of solventmodifiers facilitate the dissolution of the active agent and formationof the weak association which enable the complex of activeagent-modifier to pass the defenses of the skin with minimal irritationwithout modification of the chemical structure or stereoscopicconfiguration of the active agent.

Thus, particularly favorable results have been obtained by using as thesolvent modifier one or more of lemon oil (or/and d-limonene), VitaminE, Pro-Vitamin B, D-Panthenol and methylsulfonylmethane (MSM).

The amount of solvent modifier will be selected to result in the desiredsolute/solvent ratio, and will depend on various factors, including, forexample, primarily, the polarities, and polarizabilities, dipolemoments, van der Waals forces of each component, including the solvent,solvent modifier and solute (active agent).

In this regard, in order to match the polarities, dipole moments, of thesolute to that of the solvent system the amount of the individualcomponents of the solvent system will be selected such that the weighted(molar) average of the dipole moments of the individual components willbe substantially the same as the dipole moment of the solute insolution.

Generally, the suitable amount of solvent modifier(s) to achieve thedesired solute/solvent ratio will fall within the range of from about0.0001 to about 50%, preferably, from about 0.1 to about 35%, morepreferably, from about 0.1 to about 5%, based on the total composition.

(C) Solute Modifiers

The solute modifier may be included in the formulation of the topicaldelivery system where necessary to facilitate dissolution of insolubleor sparingly soluble solutes at higher concentrations. Solute modifierswhich form reversible or temporary complexes with the solute tofacilitate passage through the skin while minimizing immunologicalresponse are especially effective. The solute modifier will also,optimally, be a nutritional compound which will metabolized by the bodyonce the solute is released from the complex.

Examples of preferred solute modifiers include, for example, terpenes,such as, for example, Uncaria Tomentosa (“Cat's Claw”),oxindolealkaloids, quercitrin (glycoside of quercitin), genistein andits glucoside, genistin, polyphenolic flavinoids, such as found inconcentrated grape seed extracts, scutellarein and other sugar adductgluconurides, such as, scutellarin, trans-ferulic acid, alpha-lipolicacid, sterol, such as, for example, cholesterol and cholesterol-likecompounds and hormones, such as isoflavones, 3,3′-thiodipropionic acid(sulfurated propionic acid), phosphatidyl serine and choline, VitaminD₃, Vitamin K₁, dehydroepiandosterone (DHEA). Still other suitablecandidate compounds include, for example, berberine, piper nigrurn(e.g., Bioperin®), phosphatidyl serine, phosphatidyl choline. Anothergroup of candidate compounds include boswellic acid, hypericum, phyticacid.

The selection of the particular complexer will facilitate movement ofthe solute-complex past the stratum corneum and viable skin to itsoptimal targeted internal circulation system of blood, lymph or neural;or past the vascular system, to anchor the bio-active agent, if sodesired, deep in the tissues.

The suitable amount of the solute modifier may be determined based onsuch factors as, for example, solubility of the modifier in the system(e.g. solvent plus solvent modifiers), its molecular compatibility withthe solute, its ability to modify the polarizability of the solute toincrease the concentration (solubility) of solute in the solvent, etc.Generally, the amount of solute modifier will be at least about 0.003%,such as, for example, from about 0.003 to about 5%, preferably fromabout 0.1 to about 5%, especially preferably from 0.1 to about 4%, basedon the weight of total composition. Furthermore, it is especiallypreferred that the amount of solute modifier or modifiers is equivalentto the amount of solute to provide a 1:1 interaction betweenmodifier(s): solute.

In general, the above described modifying agents, i.e., solvent andsolute modifiers, as well as other components of the solvent/carrierdelivery system of this invention should preferably be selected fromsubstances which the body recognizes as usable building blocks of otherphysiological systems. This selection therefore facilitates nearlycomplete disassociation of the medicament from the delivery system oncein the body. Since these carrier/complex compounds are reducible toelemental building blocks of physiology they should do no harm to thebody.

(D) Source of Cellular Activation Energy

The process by which transdermal drug delivery operates involves movingmolecules across chemical and electrical gradients. Under ordinary tonicconditions, the introduction of materials through the skin results inchemical cascades that consume relatively large amounts of energy as thebody seeks to defend itself against the challenge. Therefore, thetopical transdermal delivery system of the present invention, accordingto one preferred embodiment, includes a substance which brings storedenergy or the stimulus for release of stored energy on a cellular level,thereby minimizing energy- negative reactions, which could lead tosensitization, ACD or anaphylaxis. By including such stored energysubstance, there is a multiplied net increase in available cellularenergy and, accordingly, the potential acceleration of those reactionswhich result in the active agent ultimately reaching its target andbeing effectively utilized by the body.

While the composition may be formulated to utilize adenosine diphosphate(ADP) or nicotinamide adenine dinucleotide (reduced form) (NADH) orflavin adenine dinucleotide (reduced form) (FADH₂) such compounds tendto be unstable and, therefore, are often not preferred.

There has been identified a group of botanical compounds which, due,apparently, to so-called signaling mechanisms, induce highconcentrations of enzyme-substrate complexes to be formed, such as byactivation of the N_(S) (stimulatroy) protein of adenylate cyclase,thereby resulting in cellular levels of adenosine 3′,5′-cyclicmonophosphate (cAMP) approaching the maximal limits of cellular cAMPconcentration.

In particular, extracts of the plant Coleus Forskholi, and especially,Forskolin, a labdane diterpenoid, have been found to have a particularability to stimulate the production of cAMP in cells (Refs. 14 and 15).Other extracts of Coleus Forskohli, such as, Colforsin or coleonol, forexample, may also be used.

Other examples of activation energy sources for stimulating generationof cAMP, either via precursors or cellular activators, include, forexample, methyl anthines, Saikogenin and Saikosaponin, Angelaciedahuricae radix (yielding angelic acid), phelopterin, oxypeucedanin.

Examples of substances which stimulate cellular production of cGMPinclude acetylcholine, cytidene diphosphocholine and ascorbic acid(Vitamin C).

The amount of the activation energy source will depend on such factorsas, for example, the mechanism of action of the active agent, energy ofactivation (positive or negative) when active agent encounters itsintended receptor (to enhance or decrease cAMP or cGMP levels), etc.Generally, suitable amounts of forskolin or acetylcholine or othersource of cellular activation energy, will fall within the range of fromabout 0.001 to about 0. 1%, preferably, from about 0.001 to about 0.01%,more preferably, from about 0.001 to about 0.005%, based on totalcomposition. As will be appreciated by those skilled in the art, cGMP isconsidered an antagonist for cAMP. cGMP stimulation will generally beappropriate for situations where it is desired to enhance immunefunction, such as lymphocyte mediated cytotoxicity, during infection,carcinogenesis, etc. Conversely, cAMP stimulation is generallyappropriate in situations where immune system modulation is desired.

(E) Skin Stabilizers

Skin stabilizers may be included in the compositions of this inventionto stabilize the skin prior to passage and to assist the skin to repairany damage resulting from the transmigration of the active agent andsolvent and other components of the formulations.

Suitable skin stabilizers may provide one or more of the followingattributes to facilitate safe and effective dosing of the active agentwhile avoiding local or systemic sensitization: form hydrogen bonds andcomplex with free radicals: act as a bridge for collagen, keeping thestrand intact temporarily during repair; stimulate the body's repairmechanisms, modulating prostaglandin, cytokines and the like;re-stabilze the Elastin complex after the composition passes through theskin; carry cationic potential, stimulating nerve transmission, i.e.,decreasing nerve repolarization time at synapses. In addition, preferredskin stabilizers should be able to be metabolized by the body and shouldalso shield the medicament or other active agent from the skin's defensemechanisms by forming suitable complexes which will be readilyuncompleted when the active agent reaches it's intended site.

Examples of substances which may function as skin stabilizers and whichmay be included in the compositions of this invention include glycerinmonolaurate (e.g., as Lauricidin®) and similar fatty acid esters,Vitamin D₃, alkoxy glycerols, unsaturated fatty acids, such as,eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), andgamma-linolenic acid (GLA), Vitamin E (alpha tocopherol) and the esters,e.g., acetate, and derivatives thereof, e.g., tocotrienol, D-panthenol,phytantriol, dehydroepiandosterone (DHEA), pregnenolone, pregnenoloneacetate, esculin, allantoin, ascorbyl palmitate, and the like.

Suitable amounts of the skin stabilizers may be determine based on suchfactors as, for example, type of reaction between drug (active agent)and skin, between solvent and skin, etc. Generally, amounts of skinstabilizer, when present, will be at least about 0.01%, such as, forexample, from about 0.05 to about 5%, preferably, from about 0.1 toabout 5%, more preferably, from 0.1 to about 2%, by weight, based ontotal composition. It is preferred to select stabilizers which will beeffective in stabilizing the skin at as low a concentration as possible.

(F) Other Ingredients

(i). Membrane permeability modifiers

In order to further enhance the ability of the solute to reach itscellular target the compositions of this invention may optionallyinclude substances which have the ability to provide a transitory effecton membrane permeability. Many such substances are described in thegeneral and patent literature and are often referred to as skinpenetration enhancers, percutaneous absorption enhancers and similarterms. For instance, the fatty acid esters, alkoxy glycerols, allantoin,ascorbyl palmitate, and unsaturated fatty acids mentioned above as skinstabilizers may also sometime be effective to temporarily enhance cellmembrane permeability.

Other useful membrane permeability enhancers which have a transitoryeffect include, for example, Quaternium 28, Quaternium 18, and othercationic quaternary ammonium compound surfactants or emulsifiers,sulforaphen, cineol terpinen-4-ol, N,N′-diethyl ethanolamine,N,N′-dimethyl ethanolamine, and the like.

When used, amounts of the membrane permeability modifiers may range fromabout 0.01 to about 5%, preferably, from about 0.01 to about 4%, morepreferably, from about 0.05 to about 2%, based on the weight of totalcomposition.

(ii). Enzyme Activators/Signalling Compounds

Substances which function as signalling agents, namely, to provide asignal to the target cell or tissue but without crossing the cellularboundary either intact or as fragment but which facilitate the uptake ofmedicaments or other bio-active agents, such as by stimulating aparticular intercellular response, may also be included in the subjectcompositions.

In particular, mention may be made of substances which modulateenzyme-substrate (ES) complexes to change the velocity of reactions andthe resulting kinetic energy, such as, for example, the relativesaturation of the enzyme by the substrate. In addition to the abovementioned functions, Forskolin, sulforaphen and sulforaphane arebelieved to function as such enzyme activators/signalling compounds, byacting as catalysts for the ES reaction, thereby yielding more rapidorientation of ES completes to cellular receptors. (see, e.g. Ref. 13,Chapter II, pages 235-253).

Suitable amounts of such enzyme activators/signaling compounds willusually be in the range of from about 0.01 to about 0.05%, preferably,from about 0.01 to about 0.02%, by weight, based on the totalcomposition.

(iii). Capillary Dilators

Compounds which function as capillary dilators may also be included inthe subject formulations to facilitate passage of the activeagent-complex through the skin and/or provide additional capillarysurface area to facilitate uptake of the active agent into the vascularsystem. Compounds which may be incorporated to function as capillarydilators should be of low toxicity and readily reversible; suitablecompounds include, for example, in addition to know vasodilators,saponins, Quaternium 28, and sulforaphen. Preferred compounds should beable to sequentially open and close (“unzip/zip”) the hydrogen bonds inhyaluronic acid (HA) of elastin as the complexed active agent passesthrough the skin.

Suitable amounts of capillary dilatory, when present, may range fromabout 0.1 to about 2%, preferably, from about 0.1 to about 1.5%, byweight, based on the total composition.

Formulations

In formulating a carrier system of solvent, modifying agents, includingsolvent modifier and solute modifier, and other components, for thetransdermal delivery system of this invention, several factors may beconsidered in selecting the particular ingredients to be included. Forexample, such factors as (1) the availability of pure drug versus a saltof the drug; (2) the solubility of the active agent (usually solubilityof a solute in a solvent may be predicted by the relative dipolemoments, the closer in value the more soluble will be the solute); (3)whether or not an ingredient will form an adduct or otherwise react withor degrade the solute or the complex of solute-solvent; (4) commonstructural features and physical characteristics of solute and solvent;(5) hydrophilic/lipophilic balance (for non-polar solutes); (6) pH(should be matched to that of the active agent, generally in the rangeof from about 2.5 to about 8.0, preferably 3.0 to 6.0, especially fromabout 3 to 4, especially for acidic active agents and/or to minimize orrelieve pain on the exposed skin where the composition is applied; pHmay be increased or decreased depending on the active agent, e.g., toprevent ionization or salting effects; the compositions may often beformulated to be self-buffering but, if necessary, pH may be adjusted byaddition of appropriate acids or bases, or by addition, for example, ofquaternary compounds, ethylene diamine tetraacetic acid, or the like).

The topical transdermal delivery system of this invention is preferablyin the form of a lotion or similar free flowing liquid (e.g., solution,emulsion, etc.). Due to the very rapid absorption and uptake of theactive agent the lotion may be directly applied to the skin withoutaccommodating for product runoff. For example, in most cases theformulation is rapidly absorbed in to the skin within a few to severalseconds after application and with a high e.g.) 90%) percentage of theactive agent being transmigrated and made bio-available.

However, if desired, various additives, such as thickeners or gellingagents may be incorporated to form gels or creams according to standardpharmacological and cosmetic technology. Alternatively, the topicaltransdermal composition may also be incorporated into a TDD system,e.g., patch. However, in all of these modified forms it is expected thatthe efficiency of delivery will be impaired with regard to rate ofabsorption and amount of active agent delivered. Therefore, it isgenerally preferred to exclude gelling or thickening agents and to applythe formulation as a liquid (lotion) directly to the skin rather than asa component of a patch system or directly as a gel.

A standardized or Stock Delivery System (SDS) for the solvent/carrierdelivery system which as been found to be effective for a wide range ofdrugs and other active agents is set forth below. In the following tablethe “amount” of each ingredient is on the basis of an approximately 2liter system. The amount of the active ingredient or ingredients whichmay be incorporated into the SDS will depend on the nature of the activeingredient, but generally may range from about 0.1 gram to about 100grams, preferably from about 0.1 to about 60 grams per liter of SDS,more preferably, at least about 0.25 gram, especially at least about 0.5gram, such as from about 1 to about 45 grams or more, per liter of SDS,corresponding to a 1 cc unit dosage of from about 0.1 to 100 mg,preferably from about 0.1 to 60 mg, more preferably at least about 0.25mg, especially at least about 0.5 mg, most especially at least about 1mg, per cubic centimeter (cc). These ranges apply for both biological(e.g., drug) and non-biologicl (e.g., cosmetic) active ingredients.

Amount Compound Function Broad Intermediate Specific Units Ethanol,i-propanol, solvent 1000-1200 1050-1150 1125 cc or sec-butanol Propyleneglycol solvent 700-900 750-850 800 cc Natural Lemon Oil solvent modifier1-3 1.5-2.5 2.0 g D-Panthenol solvent modifier 0.5-1.5 0.7-1.2 1.0 gMethyl sulfonyl solvent modifier 1-3 1.5-2.5 2.0 g methane GlycerolMonolaurate skin desensitizer  2-10 3-8 5.0 g Vitamin D₃ skin stabilizer0.01-0.5  0.04-0.25 0.1 cc Uncaria Tormentosa solute modifier 1-31.2-2.5 2.0 g (15% polyphenols) (3% oxinodoles) 3,3′-Thiodipropionicsolute modifier 0.5-2   0.7-1.6 1.0 g acid Foreskolin (pure) or Sourceof ATP 0.01-1   0.02-0.6  0.1 g Forskolin 0.1-2.5 0.1-2.5 1.0 g (extract40%)

The above Stock Delivery System may be modified, generally, as a firstapproximation, as a function of the polarity of the active agent. Wherethe solute is soluble in the alcohol/glycol solvents at the desiredlevel no further solvent modification, as such, may be required.However, it is often preferable in such case to modify the system toallow even higher dissolved solute concentrations so that smaller unitdose or less frequent applications are feasible.

In this regard, it is understood that the dipole moment of a givencompound may be taken directly from the literature, when available, orotherwise measured or calculated by standard techniques, includingcommercially available chemical modeling software packages. Generally,dipole moment is experimentally determined for an element or compound bysuspending a molecule in an electromagnetic field by measuring theamount of energy (torque) to rotate the molecule one rotation. Dipolemoment is correlated to van der Waals forces and the number of hydrogenbonds as well as electrostatic energy of a molecule. Two chemicalentities with approximately the same dipole moment will usually have anaffinity for and be attracted to one another without the necessity forcovalent bonding.

To determine the dipole moment of the solvent(s) and modifiers, aweighted average of the dipole moments of the individual components isused. The weighted average should closely approximate the dipole momentof the solute. The closer the match the faster will be the rate oftransmigration through the skin. Generally, the Stock Delivery Systemwill be modified, as necessary, to move the dipole moment of the solventsolution with modifying agents and other additives, including thesolute, to as close as possible to that of the solute, preferably within15%, especially within 10%, most especially within 5%, of the dipolemoment of the solute.

More specifically, in accordance withe preferred method for forming thecompositions of this invention, especially for increasing the amount ofdrug or other active ingredient which can be stably carried to solutionin the inventive transdermal delivery compositions, the selection of andthe amounts of the ingredients of the solvent system and otherfunctional additives may be determined, in the first instance, bybalancing the dipole moment of the active agent relative to the dipolemoment of the final composition. The dipole moment of the finalcomposition is taken to be the weighted average dipole moments of eachindividual ingredient. The weighted average is obtained by calculatingthe sum of the mole-moments of each ingredient, where the mole-moment isobtained by multiplying the amount, in moles, of an ingredient, in agiven volume, e.g., 100 cc, by the dipole moment for that ingredient.For purpose of this calculation it is assumed that each ingredient inthe compositions acts independently of the other ingredients. Thus, forexample, the dipole moment of any particular ingredient does not takeinto account the electronic, e.g., repulsive or attractive, effects ofother ingredients. However, by taking concentrations into consideration,that is, by multiplying individual dipole moments by molarconcentrations, a reasonable approximation of the matching of thesystem's properties with that of the solute will generally be achieved.

As will be described further below, closer and more accurate matching orfine-tuning of the solute and delivery system may be achieved by takingother molecular characteristics into consideration.

It is also understood that for the above Stock Delivery system, thestated amounts may be varied, for example, by as much as about ±2.5% ormore, depending on the particular active agent, and the desired degreeof matching of dipole moments, and/or, other molecular properties,particular van der Waals forces, as discussed above and below. One ormore of the compounds listed above may be omitted or replaced by afunctionally equivalent compound. Some of the ingredients may alsoprovide functions in addition to those stated in the table.

For example, glycerol monolaurate, commercially available under thetrade name, Lauricidin®, my be replaced, in whole, or in part, by otherlong chain fatty acids or esters. 3,3′-Thiodipropionic acid is primarilyeffective to promote delivery of amino acids, glycosides and sugars and,for other types of active agents, may be omitted, or replaced with otherpropionic acid derivatives. Similarly, Uncaria Tormentosa (Cat's Claw)is primarily effective in delivery systems for primary alkaloid andterpenoid active agents, and may be replaced with similar terpenoids,oxindolealkaloids, polyphenolic flavinoids, etc. Vitamin D₃ alsofunctions to sweep toxins and enhances Na/K and Mg/Ca pumps.

In addition to the above ingredients the Stock Delivery System may alsoinclude, for example, phytantriol which has a similar function tod-panthenol, namely, as a solvent modifier and for its ability tofacilitate refraction from hyaluronic acid (HA) in skin. When added tothe stock formulation its typical amount is about 1.0 g (per 2 liters).

Dehydroepiandosterone (DHEA) is another highly useful solute modifier.When incorporated in or added to the SDS it is usually effective inamounts of about 100 mg (per 2 liters). Other optional, but often usefulcomponents which may be included in or added to the above SDS include,oily substances, for example, conjugated linoleic acid (CLA), mediumchain (e.g. C₆-C₈) mono-, di-, or tri-glycerides, olive oil, Emu Oil, orMelaleuca Oil (preferably 100% purity) to increase the saturation pointof the system but without facilitating supersaturation;N,N-diethylethanolamine or N,N-dimethylethanolamine, effective formodifying dipole moment and aiding in complexing of solute to modifiers,as well as a skin penetration enhancer; pregnenolone or pregnenoloneacetate, as a drug complexer and/or for increasing transdermal migrationand/or skin stabilization; transferulic acid and alpha lipolic acid, asanti-oxidants and for controlling the re-complexing of the HA in elastinand skin, also functioning as a solute complexer; Berberine, as asignaling mechanism for enhancing more efficient uptake of certainmedicaments by cells.

It is understood that the above are only exemplary of suitable additivesand modifications to the transdermal delivery systems of the inventionand that other additions, deletions or modification can be made withinthe guidelines provided herein and by the more detailed examples offollow.

While the Stock Delivery System as above or appropriately modified forthe particular active agent of interest will usually be formulated inlarge size batches the compositions of this invention including theactive agent will often preferably be provided for dispensing in unitdosage forms, as well known in the art. For example, individual sealedpackages or metered dosage pump type containers for dosing about 1 cc ofcomposition, may be provided to contain sufficient active agent for asingle application.

Laminar matrix transdermal systems are designed to leech medicamentthrough the stratum corneum into the dermis and the vicinity of thecutaneous plexis of the capillaries. This is a slow process, usuallyrequiring hours to days to deliver the maximum available dose. Sincedeep penetration is generally not possible for these systems withoutexternal iontophoretic accelerators, they are limited to delivery ofmedicaments which are systemically efficacious in relatively smalldoses, and generally only deliver one third of the drugs with which theyare loaded.

In contrast, the transdermal delivery system of this invention caneffectively delivery at least about 90% or more of the medicamentrapidly through the skin to the underlying fatty tissue. This deliverymay be accomplished in only a few to several tens of seconds or just afew minutes or less. In some cases, it may be desirable to slow down therate of trans-migration, for example, to direct the dose of themedicament for systemic administration via the capillary net of thedermis. Particular medicaments or which systemic administration is oftenindicated include, for example, hormones, vitamins, systemicantibiotics.

Such slowing down may be accomplished by modifying the stock deliverysystem so that there is mismatching of the dipole moments of the soluteand the solvent(s) and modifying agent(s), for example, at least about15% or more difference, such as about 15 to about 35% variation,especially from about 20 to 30% variation. By so varying the dipolemoments and/or other molecular characteristics, of the solute and theSDS for the solute a more shallow penetration of the solute and/or aless acute uptake curve may be achieved. Here too, however, theresulting complex of the solute with the SDS components will effectivelyshield the medicament (active agent, solute) from the body's defenses,yet will not “slip” through quite as effectively or efficiently. Thisdipole moment mismatching, may therefore, be effectively utilized toinsure that, at any given time, more medicament is in the generalvicinity of the cutaneous plexis and available to be picked up by thecapillary network for systemic delivery.

In the case of therapy requiring slower delivery, the system may bebalanced to take longer to get to the strata of the target, byemphasizing lipophilic binding affinities in the solute modifiers. Somemedicaments may safely be moved past the cutaneous plexis and stored inthe fascia beneath the capillary net. This level is not as well definedby cell-mediated immune response and may serve as a natural storage andrelease matrix for delivery of these medicaments.

Slower transmigration and/or bioavailability may also often be achieved,for example, by modifying the hydrophilic-lipophilic balance (HLB) ofsolute modifiers and/or by “shielding” the medicament with lipids whichwill increase the time to de-complexing of the solute-modifying agentcomplex.

While the above discussion focuses on the matching of the dipole momentof the active agent with the SDS, e.g., solvent(s), solvent modifier(s)and solute modifier(s), and will allow one skilled in the art toeffectively formulate topical delivery systems according to theinvention, still further refinements, and improved consistency, may beobtained by further taking into consideration other parameters which arecharacteristic of the physicochemical properties of the solute (activeingredient, e.g., drug) and the carrier components of the topicaldelivery system. In particular, the following properties of the soluteand the delivery or carrier system can be measured or calculated or may,in some cases be obtained directly from the published literature:entropy, enthalpy, Free energy, Potential energy, Kinetic Energy. DipoleMoment, Surface Interaction parameters. Matching these variousparameters between the solute and the delivery system will facilitatethe transdermal delivery of the solute to the intended target.

More particularly, the following is a more specific overview of how thesolvents, modifying agents and other enhancing agents and additives maybe compounded together to standard stock delivery carrier system and howany particular medicament molecule (or other active agent) is evaluatedand the delivery system consequently modified to maximize solubility andoptimize transmigration to the target level of skin or tissue.

Many molecular properties come into play with molecules in closeproximity. A representative list of these includes stearic energy, heatof formation, dipole moment, charge density, non-bonded energy, COSMOsolvation in water, electrostatic potential, electron spin density,hyperfine coupling constants, atomic charges, polarisability and otherssuch as IR vibrational frequencies. According to the present invention,the molecular evaluation system is particularly concerned with 4 of theseveral forces in play on the molecules of the system and themedicament. These four elements are:

Electrostatic Energy

Non-bonded Energy

Polarisability

Hydrophobic Bonding

These four elements constitute a graded, increasingly fine approximationto balance of those factors and vectors which are predictive ofdissolving a particular medicament in a liquid medium, the aggregationof which is designed to rapidly transmigrate the lipid domains of the SCby means of temporary disruption, continue traverse through the VS tothe capillary plexis beneath or past the plexi into the fascia lata ordeeper as required, the entire process being accomplished so as toassist in repair of damage secondary to domain modulation andminimization of hapten formation and any subsequent cascade.

Electrostatic Energy

The Electrostatic energy which is the first parameter of intermolecularforces which may be controlled can be described with the equation:$E_{E\quad l\quad e\quad c\quad t\quad r\quad o\quad s\quad t\quad a\quad t\quad i\quad c} = {\sum\limits_{i}{\sum\limits_{j}\frac{q_{i}q_{j}}{D\quad r_{ij}}}}$

where the Electrostatic energy is a function of the charge on non-bondedatoms, q; their inter-atomic distances, r_(ij) and a moleculardielectric expression, D, which accounts for the attenuation ofelectrostatic interaction by the environment, e.g. between the solventand solute modifiers and between the system and the medicament itself.

In a preferred embodiment, the electrostatic energy may be modeled bythe Chem 3D software, available from Cambridge Soft Corporation,Cambridge, Mass., using atomic charges for charged molecules and bonddipoles for neutral molecules. There are three interactions which areaccounted for through the Chem 3D software. These include Charge/Chargeinteractions; Dipole/Dipole interactions; and Dipole/Chargeinteractions. These interactions are calculated for each molecule of thecarrier system and the medicament separately and then a weighted molaraverage calculation accounts for the system as a whole, and thisquotient is balanced against the medicament as to gross order ofmagnitude. Each type of interaction uses a different form as shownbelow:

Charge/charge contribution:$E = {332.{\sum\limits_{i}{\sum\limits_{j}\frac{q_{i}q_{j}}{D\quad r_{ij}}}}}$

where the value 332 converts the results to units of kcal/mole.

Dipole/dipole contribution:$E = {14.4{\sum\limits_{i}{\sum\limits_{j}{\frac{\mu_{i}\mu_{j}}{D_{\mu}\quad r_{ij}}\left( {\cos - {3\cos \quad \alpha_{i}\cos \quad \alpha_{j}}} \right)}}}}$

where the value 14.4 converts the result from ergs/mole to kcal/mole, isthe angle between the two dipoles, μ_(i), and μ_(j), α_(i) and α_(j) arethe angles which the dipoles form with the vector r_(ij), connecting thetwo at their midpoints, and Dμ is the effective dielectric constant.

Dipole/charge contribution:$E = {69.1{\sum\limits_{i}{\sum\limits_{j}{\frac{q_{i}\mu_{j}}{r^{2}{ij}\sqrt{D_{\mu}\quad D_{q}}}\left( {\cos \quad \alpha_{j}} \right)}}}}$

where the value 69.1 converts the result to units of kcal/mole.

Bond dipole parameters, _(μ), for each atom pair are stored in bondstretching parameter table of the Chem 3D software or may be obtainedfrom the literature or other available databases, such as, for example,Cambridge Structure Database, or experimentally. The charge q is storedin the Molecular Mechanics (MM2) atom types table. The moleculardielectric is set to a constant value between 1.0 and 5.0 in the MM2Atom types table.

Non-bonded Energy

The second parameter which may be manipulated and balanced is Non-bondedEnergy. Molecular mechanics describes the energy of a molecule in termsof a classically derived potential energy functions and the parametersused for their evaluation are known as “force field” parameters.Molecular mechanical methods are based on the following principles:

Nuclei and electrons are lumped together and treated as unifiedatom-like particles.

Atom-like particles are regarded as spheres.

Bonds between particles are viewed as harmonic oscillators and thereforesubject to principles of harmonic conservation of energy.

Non-bonded interactions between these particles are treated usingpotential functions derived from classical mechanics.

Individual potential functions are used to described the differentinteractions; including bond stretching, angle bending, torsional orbond-twisting energies and non-bonded or through-space interactions (theinteractions of most concern in the subject liquid system).

Potential energy functions rely on empirically derived parameters, e.g.,force constants, equilibrium values, that describe the interactionsbetween sets of atoms.

The sum of interactions determine the spatial distribution orconformation of atom-like particles.

Molecular mechanical energies have no meaning as absolute quantities.They can only be used to compare relative stearic energies between twoor more conformations of the same molecule.

Molecular theory typically treats atoms as spheres and bonds as springs.The mathematics of spring deformation (Hooke's Law) is used to describethe ability of bonds to stretch, bend and twist. Non-bonded atomsdefined as greater than two atoms apart, interact through van der Waalsattraction, stearic repulsion, and electrostatic attraction/repulsiondescribed above. These properties are easiest to describe mathematicallywhen atoms are assumed to be spheres of characteristic equal radii.

The total potential energy, E_(TP), of a molecule can be described bythe following summation:

 E _(TP) =E _(S) +E _(B) +E _(T) +E _(NBI)

where E_(S) is Stretching Energy, E_(S) is Bending Energy, E is TorsionEnergy and E_(NBI) is Non-bonded Interaction Energy. The first threeterms are the so-called bonded interactions. In general, these bondinginteractions can be viewed as a strain energy imposed by a model movingfrom some ideal zero-strain conformation. The last terms, whichrepresents non-bonded interactions, is the variable which is of mostconcern for the present liquid compositions.

The non-bonded energy represents the pairwise sum of the energies of allpossible interacting, non-bonded atoms i and j with a pre-determined“cut-off” distance. The non-bonded energy accounts for repulsive forcesexperienced between atoms at close proximities, defined as less than 2 Åand for the attractive forces felt at longer distances, defined asgreater than 2 uniform molecular radii. It also accounts for their rapidfall-off as the interacting atoms move farther apart by a few Angstroms.

Repulsive forces dominate when the distance between interacting atomsbecomes less than the sum of their contract radii. This repulsion can bemodeled by the following equation which combines an exponentialrepulsion with an attractive dispersion interaction (1/R⁶):

E _(van der Waals)=Σ_(i)Σ_(j)ε(290,000e ^(−12.5/R)−2.25R ⁻⁶)

where $R = \frac{r_{ij}}{R_{i}^{*} + R_{j}^{*}}$

where R_(i)* and R_(j)* are the van der Waals (VDW) radii of the atoms,epsilon (ε) is the depth of attractive potential energy and consequentrelative ease with atoms can be pushed together and r_(ij) is the actualdistance between the atoms.

At short distance, the above equation favors repulsive over dispersiveinteractions. To compensate for this at short distance this term isreplaced with:

E _(van der Waals)=336.2 Σ_(i)Σ_(j) εR ⁻²

For certain interactions, values in the VDW interactions parameter tableof the ChemPro 3D software package are used instead of those in the MM2atom types table. These situations include interactions where one of theatoms is very electronegative relative to the other, such as in the caseof water.

Polarisability

The third parameter allowing for modulation towards the balance ofmedicament and carrier system is polarization. Polarisability values arecalculated by Chem3D software using the following equations. Of specialconcern is the orientation polarization (P_(d)) caused by thepreferential alignment of permanent dipoles in the direction of theelectrical, or in this case, the bio-electrical field. To compute P_(d),the magnitude of the dipole moment M induced in a molecule by the fieldacting on it must be factored in. It is assumed that this induced momentis proportional to the strength of the field F, so that:

m=αF

The proportionality factor α is called “polarisability.” It is theinduced moment per unit of field strength. Note that α has thedimensions of volume since:$\frac{Q\quad r}{\left( {Q/r^{2}} \right)} = r^{3}$

The polarisability of a hydrogen atom is 4.5a³, which is close to thevolume of a sphere of radius equal to that of the Bohr orbit, 4/3πa₀³=4.19a₀ ³. The polarisability of an atom is a good measure of itsvolume.

If the dielectric is not a gas, as is the case with the present liquidcompositions, the influence of the surrounding molecules has to beaccounted for in order to estimate the field that acts to polarize agiven molecule or atom-like particle. For gases at high temperatures,for non-polar liquids, and for dilute solutions of polar solutes innon-polar solvents, the effective field F is often taken to be:$F = {E + {\frac{4\pi}{3}P}}$

It follows then that $m = {{\alpha \quad E} + {\frac{4\pi}{3}P}}$

from which is obtained$P_{m} = {\frac{\varepsilon - {1M}}{\varepsilon + {2p}} = \frac{4\pi \quad L\quad \alpha}{3}}$

where $P = \frac{3\left( {F - E} \right)}{4\pi}$

is the polarization of individual molecules, E is electrical energy andP_(m) is called the molar polarization.

Polarization is a calculation in the X, Y, and Z planes and thenaveraged for each molecular constituent of the carrier and then for thecarrier versus the medicament. Bond stretch parameters are notconsidered. The carrier and medicament are viewed as Atom-likeparticles. For the same reason energies of vibration and librationdefined above, may be ignored.

Hydrophobic Bonding

The fourth and finest refinement of the balance is accomplished bymodulating Hydrophobic Bonding. These parameters are calculated from theaverage potential of each Hydrogen atom on each specific constituentmolecule. This last factor becomes particularly important in hydrophobiclipophilic systems and obviously critical in protein delivery, sincemethylated fatty acids replace alcohol or propylene glycol as theprimary solvent for the system. This averaged value can be seen as thecapacity of the carrier for low polarity, lipid solubility and comparesthe potential of the Hydrogen molecules on the outer surface of thesolvent and solute. Hydrophobic Bonding values may be calculated byChem3D software.

In practice, a data base on the primary, secondary, and tertiaryingredients of a standard delivery system as well as alternate solventsand modifiers for medicaments requiring a different approach such asproteins or very large polymerized molecules will be established. By“primary,” “secondary” and “tertiary” is meant ingredients which exertmajor or gross changes in system properties, e.g. dipole moments, vander Waals forces, etc. (Primary); ingredients which make only smallchanges in system properties (secondary) and ingredients which can beused for “fine-tuning” the system properties to match the properties ofthe solute (tertiary).

The following tables are typical data sheets generated by the Chem3Dsoftware. These charts confirm the independent experimental solubilitydata and also, in Tables 1-3, show how modulation of the carrier systemallows a higher dose of the test medicament, Diosgenin (MW=414.61).Table 1 shows balance (and maximum solubility) at 0.25 grams in atypical Stock Delivery System (SDS) according to the invention; Table 2shows that modulating the system by adding isopropyl alcohol increasedthe solubilized dose to 1.2 grams, a nearly 5-fold increase. Table 3shows that when the van der Waals forces of the delivery system with andwithout drug are mismatched, the system becomes unstable, namely, thesolubility limit of the drug is exceeded and a precipitate forms whenthe composition is allowed to stand overnight.

It is pointed out, however, that the formulations shown in the followingTables, and which are based on the above described Stock DeliverySystem, were originally prepared without benefit of the use of the Chem3D software and included omission of several different modifiers.Modifications to the SDS to effect solubilization and increase solutesolvent ratios were made by the inventor on the basis of knowledge ofhow and where the solute (drug) works in the body and using thisinformation to make intuitive predictions of how the solute wouldinteract with the surrounding molecules of the SDS, such as inducedpolarities relative to other molecules; induction of electric fields dueto influence of surrounding molecules; hydrophobic versus hydrophilicproperties, etc., while always taking into consideration the desiredfunctional effects contributed by each ingredient. Thus, it should beunderstood that these tables provide a more rationalized basis andunifying theory of the operation of the invention and should allow forpreparing stable compositions containing different solutes at highsolute/solvent system ratios. For example, using computer modeling ofchemical structure can often facilitate understanding ofpolarizabilities and possible interactions between the drug and otherpotential components of the system. Again, any potential component mustbe compatible with the active agent, namely, not form or induce achemical reaction or covalent bonding.

For any medicament to be delivered, similar numbers may be generatedwhereby the carrier system will be balanced against the medicament.

It will be appreciated that the modifications and calculations in thetables follow the same general principles as described previously forbalancing dipole moments using the sum mole-moments. In this case, it isthe sum of the mole- van der Waals forces which is calculated and whichappears to provide an effective correlation and predictor of success informulating stable compositions with high solute/solvent ratios.

It should also be appreciated that the use of computer software, forchemical structure modeling, such as Chem3D software, while speeding upthe ability to fine tune the transdermal delivery system, is notessential since solubility and other data can generally be obtained fromthe literature or by direct experimentation, using the generalguidelines and concepts discussed previously.

As in the case for balancing of dipole moments, in the presentinvention, the formulation of the solvent carrier system, which may bethe above described SDS or any other appropriate non-aqueous or aqueoussolvent-carrier system for the particular active agent or active agentsand the particular disease or other condition to be treated, may bebalanced for mole-van der Waals forces, when the active agent or agentsare added thereto, as a predictor of solubility of the desired amount(s)of active agent(s) by bringing the sum of the mole-van der Waals forcesfor the solvent carrier system with active agent(s) to within ±20%,preferably within ±15%, especially preferably within ±10%, and mostespecially preferably within ±5%, of the sum of the mole-van der Waalsforces of the solvent carrier system without the active agent(s).

When the difference between the sum of the mole-van der Waals forces ofthe solvent carrier system plus active agent is greater than about 20%,especially greater than about 15%, of the sum of mole-van der Waalsforces for the solvent carrier system without active agent the desiredamount of active agent will tend to be insoluble in the solvent carriersystem or may precipitate from solution upon standing overnight. In thecase of compositions containing two or more active agents, if themole-van der Waals forces are not closely balance, as described above,one or more of the active agents will tend to be insoluble in thesolvent carrier system or otherwise precipitate out of solution.

TABLE 1 Diosgenin Base Solution Moles Amt. VW Compound Mole Wt. (grams)Amt./100 cc Moles Forces VW Forces Diosgenin 414.6 0.25¹ 0.0006 26.880.016 Ethanol 46.07 1068.75 54.38 1.18 2.01 2.375 Water 18 56.25 2.860.16 0 0 Propylene Glycol 76.01 828 42.13 0.55 4.10 2.272 limonene136.24 2 0.10 0.0007 6.22 0.0046 Vitamin E 430.17 1 0.50 0.00012 20.600.0024 D-Panthenol 205.25 1.05 0.05 0.00026 10.82 0.0028 Methylsulfonyl-94.13 2 0.10 0.0011 −0.34 −0.0004 methane (MSM) Lauriciden 181.97 5 0.250.0014 14.04 0.020 Oxindole 295 0.06 0.003 1.0E−05 13.66 0.0001Thiopropionic 178.21 1 0.05 0.0003 6.61 0.001 acid Forskolin 410 0.20.01 2.5E−05 25.05 0.0006 Totals 1965.31 100 stock solution + = 4.694diosgenin stock solution w/out 4.678 diosgenin = difference = 0.016percent difference = 0.34% ¹Solubility limit determined experimentally

TABLE 2 Diosgenin System One Mole VW Amt/ VW Forces Compound Mole Wt.100 cc Moles Forces One Diosgenin 414.6 1.2¹ 0.003 26.88 0.078 Ethanol46.07 77.73 1.69 2.01 3.395 Isopropyl Alcohol 60.1 8.18 0.14 1.94 0.264Water 18 2.30 0.13 0 0 Propylene Glycol 76.01 10.04 0.13 4.10 0.541limonene 136.24 0 0 0 Vitamin E 430.17 0 0 0 D-Panthenol 205.25 0 0 0MSM 94.13 0 0 0 Lauriciden 181.97 0.3 0.00 14.04 0.023 Oxindole 295 0.060.0002 13.66 0.003 Thiopropionic 178.21 0 0 6.61 0 acid Forskolin 4100.2 0.0005 25.05 0.012 Totals 100 Diosgenin 4.316 SysOne Mole VWF STOCKSOL. 4.238 Diosgenin SysOne 0.07 minus Stock Sol. Percent Difference1.84 ¹Stable solution; effective for transdermal delivery

TABLE 3 Diosgenin System Two Mole Amt/ VW VW Compound Mole Wt. 100 ccMoles Forces Forces Diosgenin 414.6 1.5¹ 0.0036 26.88 0.097 Ethanol46.07 77.49 1.682 2.01 3.385 Isopropyl Alcohol 60.1 8.16 0.136 1.940.264 Water 18 2.29 0.127 0 0 Propylene Glycol 76.01 10.00 0.132 4.100.539 limonene 136.24 0 0 0 Vitamin E 430.17 0 0 0 D-Panthenol 205.25 00 0 MSM 94.13 0 0 0 Lauriciden 181.97 0.3 0.0016 14.05 0.023 Oxindole295 0.06 0.0002 13.66 0.003 Thiopropionic 178.21 0 0 6.61 0 acidForskolin 410 0.2 0.0005 25.05 0.012 Totals 100 Diosgenin Sol 4.323 MoleVWF Two STOCK SOL. 4.226 Diosgenin Sys 0.097 minus Stock Sol. PercentDifference 2.30 ¹Solution not stable; precipate forms upon standingovernight.

The following Table 4 illustrates how the balancing of molar van derWaals forces can be utilized as a predictor of the solubilization ofamitriptyline in the stock delivery system. In this case thecalculations for balancing molar van der Waals forces were made firstusing the Chem3D software and the solutions were thereafter formulatedin the laboratory. The amount predicted to dissolve, 2.08 gm per 100c.c., was within experimental error of the actual amount which woulddissolve in the laboratory experiment. In this case, the system wasbalanced by increasing the amounts of methylsulfonylmethane and ethanoland decreasing the amount of propylene glycol.

TABLE 4 SDS SDS Mod. SDS SDS + Drug SDS + Drug Mole Wt Amt/100 MolesAmt/100 Moles VW Forces VDW-Molar VDW-Molar Amitriptyline 277.41 2.000.007 2.08 0.0075 15.99 0.115 0.120 MSM 94.13 0.20 0.0021 −0.39 −0.0008Ethanol 46.07 54.38 1.18 61.99 1.35 2.01 2.375 2.708 Water 18 2.86 0.161.86 0.16 0 0 0 Propylene glycol 76.01 42.13 0.55 33.70 0.44 4.10 2.2721.817 limonene 136.24 0.10 0.0007 0.10 0.0006 6.22 0.005 0.004 Vitame E430.17 0.05 0.0001 0.05 9E−05 20.60 0.002 0.002 D-panthenol 205.25 0.050.0003 0.05 0.0002 10.81 0.003 0.002 MSM 94.13 0.10 0.001 0.10 0.0009−0.39 −0.0004 −0.0003 Lauriciden 181.97 0.25 0.001 0.25 0.001 14.050.020 0.016 Oxindole 295 0.003   1E−05 0.003 8E−06 13.66 0.0001 0.0001Thioproprionic 178.21 0.05 0.0003 0.05 0.0002 6.60 0.002 0.002 acidForskolin 410 0.01 2.5E−05 0.01 2E−05 25.05 0.0006 0.0005 100 SDS + Drug= 4.794 4.670 SDS = 4.679

The following Table 5 illustrates the calculation of the mole-moment fora typical Stock Delivery System (SDS) according to the invention:

TABLE 5 SDS Dipole Mole Compound Mole Wt Amt Used Amt/l00 Moles MomentMoment Ethanol 46.07 1068.75 54.38 1.18 1.78 2.10 Water 18 56.25 2.860.16 1.85 0.29 Propylene Glycol 76.01 828 42.13 0.55 1.45 0.80 limonene136.24 2 0.10 0.0007 0.365 0.0003 Vitamine E 430.17 1 0.05 0.0001 0.8359.9E−05 D-panthenol 205.25 1.05 0.05 0.00026 4.33 0.001 MSM 94.13 2 0.100.0011 4.51 0.005 Lauriciden 184.97 5 0.25 0.0014 3.08 0.004 Oxindole295 0.06 0.003 1.03E−05 1.42 1.5E−05 Thiopropionic Acid 178.21 1 0.050.00029 3.94 0.001 Forskokin 410 0.2 0.01  2.5E−05 4.48 0.0001 1965.31100 SUM Mole 3.20 Moments

Table 6 shows van der Waals force values for various hormonal activeagents:

TABLE 6 Hormone VW Forces Testosterone 16.17 Estrone 13.74 Estradiol14.87 Estriol 13.89 DHEA 16.48 17 OH Pregnonolone 18.16 Pregnenolone16.78 Progesterone 15.93 Diosgenin 26.88

Use of the invention methodology for forming a topical composition fortransdermal delivery of hydroxyzine at a predetermined or target dosageof about 45 to 50 mg per cubic centimeter is illustrated in thefollowing Table 7:

TABLE 7 SDS¹ H-1² H-2³ H-O H-1 H-2 Mole Amt/ Amt/ Amt/ Sol Two dipoleMole VW Mole- Mole- Mole- Compound Wt 100 100 100 Moles Moles MomentMoment Forces VDW VDW VDW Hydroxyzine 374.91 5.0 5.0 4.55 0.013 0.0120.57 0.0076 22.72 0.303 0.303 0.276 MSM 94.13 2.0 1.0 0.021 4.51 0.096−0.39 −0.0080 −0.0083 Ethanol 46.07 54.38 54.38 58.07 1.18 1.26 1.782.10 2.01 2.375 2.375 2.536 Water 18 2.86 2.86 0.16 1.85 0.29 0 0 0 0Propylene 76.01 42.13 42.13 38.30 0.55 0.50 1.45 0.804 4.10 2.272 2.2722.065 Glycol limonene 136.24 0.10 0.001 0.10 0.0007 0.36 0.0002 6.230.0046 0.0046 0.0042 Vit E 430.17 0.05 0.051 0.0001 0.83 0.0001 20.000.0024 0.0024 0.0022 D-panthenol 205.25 0.05 0.053 0.003 4.33 0.00110.82 0.0028 0.0028 0.0026 MSM 94.13 0.10 0.10 0.001 4.51 0.005 −0.39−0.0004 −0.0004 −0.0004 Lauriciden 181.97 0.25 0.25 0.001 3.08 0.00414.05 0.0196 0.0196 0.017 Oxindole 295 0.003 0.003 1E−05 1.42 1.5E−0513.66 0.00014 0.00014 0.0001 Thiopropionic 178.21 0.05 0.05 0.0002 3.940.001 6.61 .0019 0.0019 0.0017 acid Forskolin 410 0.20 0.20 0.005 4.480.002 25.05 0.0006 0.0006 0.0006 4.982 4.973 4.898 ¹Initial Attemptadded Hydroxyzine to Stock Sol. ²First modification added additional MSM³Second modification increased Ethanol and reduced additional MSM

Although not wishing to be bound by any particular theory of operation,it is believed that the most adequate theory describing how themedicament finds its way, once inside the body, to the intended targetsite, is the so-called “information theory.” This theory asserts thatmedicaments are biologically active compounds for which the bodydevelops particular affinities when challenge is present due todegenerative disease, infection or trauma. The affected tissuesselectively attract and bind these substances as they encounter them inhumor or tissue mediums while normal tissues seek to deflect thecompounds away. Once the carrier medicament-complex arrives in thevicinity of the diseased or “abnormal” tissue, the attraction of thetissue receptors overcomes the weak association between the carrier andthe medicament and the medicament is released intact and taken by theneedy tissue. By a similar mechanism modifying agent components may bestripped from the complex prior to arriving at the needy tissue.

Examples of medicaments which may be incorporated in the transdermaldelivery system of this invention are not particularly limited.Generally, any medications previously used or suggested as useful fordelivery by any means, including transdermally, whether by patch orointment or other topical formulation, may be used in this invention.Some areas where it is envisioned that the subject TDS will haveparticular benefits include pain relief (for safer dose of aprescription or non-prescription analgesic locally to the site of pain);antibiotic delivery, e.g., Ciprofloxacin (permitting higher dosages atthe locus of the infection to above safe systemic levels);corticosteroids (for treating inflammatory indications with deliverybypassing the liver and minimizing systemic side effects); hormonereplacement therapy (e.g., to deliver tri-estrogens to thenon-carcinogenic androgen pathway along with the inclusion of mechanismsto offset the negative cosmetic side effects of this pathway);isoflavinoid cancer therapies (allowing high concentrations); hypertoxicchemotherapies (to raise local concentratiosn with reduced impactsystematically).

More generally, any of the drugs listed in, for example, The MerckIndex, or other pharmacopeia, may be used. For example, mention may bemade of hormones, such as, DHEA sulphate, 17-hydroxy pregnonolone,testosterone, tri-estrogen; topical anesthetics, such as, lidocaine,procaine, dimethocaine, salicylic alcoholic; analgesics, such as, forexample, morphine, Demerol®, Fentanyl®, sufentanil, acetaminophen,acetylsalicylic acid, bucetin, difenamizole, enfanamic acid, etodolac,fenoprofen, Ibruprofen, naproxen, suprofen; steroids, such as, forexample, pregnonolone, pregnonolone acetate, progesterone;ACE-inhibitors; α-adrenergic agonists; β-adrenergic agonists;α-adrenergic blockers; β-adrenergic blockers; adrenocortical steroids;adrenocorticotropic hormones; alcohol deterrents; anabolic steroids;androgens, such as testosterones; anorexics; antacids; anthelmidines;antiacne and keratolytics; antiallergic, decongestants, antihistamines,glucocorticoids; antialopecia agents; antiandrogens; antianginals;antiarrhythimics; antiarthritic/antirheumatic; antiasthmatic;antibacterial (antibiotics), e.g., Ciprofloxacine, antifungal andantiviral agents; antinenoplastics; anticholinergics; anticoagulants;anticonvulsants; antidepressants, e.g., 5-hydroxytriptophan;antidiabetics; antidiarrheal agents; antidiuretics; antidotes (e.g.,acetaminophen poisoning, cyanide poisoning, heavy metal poisoning);antisyskinetics; anti-eczematic agents; antiemetics; antiestrogens;antihistamines; antihyperlipoproteinemics; antihyperphosphatemics;antihypertensives, such as, e.g., clonidine, or other “beta-blockers”;antihyperthyroids; antihypotensives; antithypothyroids;anti-inflammatory (steroidal and non-steroidal, including, for example,the above-exemplified analgesics and other NSAIDs and steroidalinflammatories); antimalarial; antimigraines; antineoplastic agents;antiparkinsonian agents; antipruritics; antipsoriatics; antipsychotics;antipyretics; antiseptics and disinfectants, antispasmodics;antithrombotics; antitussives; antiulceratives; anxiolytics;astringents; benzodiazepine agonists; bronchodilators; calcium channelblockers; cardiotonics; chelating agents; choleretics; cholinergic;central nervous system (CNS) stimulants; digestive aids; diuretics;enzymes; estrogens; glucocorticoids; gonad-stimulating principles;gonadotropic hormones, other hormonal-type substances, such as, forexample, melatonin, serotonin, liothyronine, histamine H₂-receptorantagonists; immunomodulators; immunosuppressants; lactation stimulatinghormones; LH-RH agonists; liptropics; monoamine oxidase inhibitors;muscle relaxants; narcotic antagonists; oxytocin agents; progestogen;prolactin inhibitors; prostaglandin/prostaglandin analogs; proteaseinhibitors; sedatives and hypnotic agents; vasodilators (cerebral,coronary and peripheral); vasoprotetants; vitamins.

In particular, the present invention may offer its most notable benefitsin connection with active agents of high molecular weights for whichprior known topical transdermal delivery systems were not effective orapplicable. Thus, the compositions of this invention are highly usefuland effective for active agents having molecular weights in excess ofabout 325 Daltons, especially higher than about 350D, more especiallyhigher than about 375D and most especially higher than about 400D, forexample, 500D and higher. Extremely high molecular weight substancessuch as calcitonin (MW=4500); human growth hormone (MW=22,000) and otherhormones, polypeptides and protein, may be solubilized in accordancewith this invention by appropriate selection of solvents, e.g., fattyacid, and utilizing appropriate phospholipid chemistry for the oil phaseand hydrophilic/lipophilic modulation by appropriate modifying agents.Moreover, the compositions of this invention may be formulated todelivery, per unit dosage, usually about 1 cc, at least about 0.25 mg,especially at least about 0.5 mg, especially, up to about 1 mg or higherof active ingredient, including such high molecular weight substances asdescribed above.

Moreover, the effective dosage of the medicaments are generallysubstantially less than the effective dosage when administered orally orintravenously or intramuscularly; and a rule of thumb is that topicaltransdermal dosages are approximately one-seventh of the oral dosage.However, higher or lower dosages may be required or advantageousdepending on the symptoms, whether intended for local or systemicadministration, etc.

The invention will not be described with reference to the followingnon-limiting illustrative examples.

In the following examples the above described SDS was used, in theamounts indicated. Unless otherwise noted all of the ingredients are USPgrade.

EXAMPLE 1

The following composition (lotion) using the above described StockDelivery System (SDS) is prepared with Diosgenin(25R)-Spirost-5-en-3β-ol) as active ingredient; diosgenin is a large(MW=414.6), difficulty soluble soy isoflavone:

Compound Function Amount (grams) Diosgenin Active 4.5 95%Ethanol/Sec-butanol Primary Solvent 410 c.c. SDS Primary Delivery  90c.c. Alpha lipoid (Thioctic) Acid Complexer 0.5 Methyl Sulfonyl MethanComlex Former 0.5 3,3′-Thiodipropionic Acid Complexer 0.2

A second lotion incorporating other soy isoflavanone compounds isprepared as follows:

Compound Function Amount (grams) Genistein Active 5.0 Daidzein Active5.0 Biochanin A Active 5.0 Phosphatidyl Serine Complexer  25 c.c. SDSPrimary Delivery 500 c.c.

In the above formula, daidzein is 4′,7- dihydroxyisoflavone. Biochaninis the 4′-methyl ether of genistein(5,7-dihydroxy-3-(4-hydroxphenyl)-4H-1 bensopryran-4-one;4′,5,7-trihydroxyisoflavone.

These two formulations when used in combination, are expected to beuseful in the treatment of prostate cancer.

EXAMPLE 2

A hormone replacement therapy formulation, especially useful in thetreatment of Benign Prostatic Hyperplasia (BPH) using a lowerconcentration of soy isoflavanones, than in the formulations of Example1, again in the form of a lotion, is prepared with the followingingredients:

Compound Function Amount (grams) SDS Primary Delivery 500 c.c. DiosgeninActive 2.5 Dehydroepiandosterone Skin Stabilizer/Active 7.5 Pregnenoloneacetate Skin Stabilizer/Active 1.25 Dopamine Tonic 0.1 Para-aminobenzoicAcid B Complex Former, 0.5 Skin Stabilizer 2-Diethylaminoethanol SoluteModifier 0.5 Ascorbyle Palmitate Solvent Modifier 0.15

To enhance the cosmetic tonic properties of the above formulation,various cosmetic additives can be added to the above formula, forexample, various plant extracts, such as, for example, extracts ofcamomile, rosemary, rose hip, horsetail, in amounts of, for example, 10cc, 5 cc, 5 cc, and 5 cc, respectively.

EXAMPLE 3

A similar, but milder, formulation to that of example 2, more suitablefor a female cosmetic product is formulated as follows:

Compound Function Amount (grams) SDS Primary Delivery System 300Pregnenolone acetate Skin Stabilizer/Active 1.0 Diosgenin Active 0.6Dehydroepiandosterone Skin Stabilizer/Active 0.6 Forskoli (extract, 40%)65 mg. 3-Hydroxy Tyramine Tonic 50 mg. (Dopamine) Camomile Extract Tonic5.0 cc Ascorbyle Palmitate Solvent Modifier 0.3 Para-aminobenzoic acid BComplex Factor, Skin 0.5 Stabilizer 2-Diethylaminoethanol SoluteModifier 0.5 Horsetail Extract Tonic 0.5 3,3′-Thiodiproprionic acidSolute Modifier 0.075 Methyl Sulfonyl Methane Solvent Modifier 0.5

EXAMPLE 4

The following female tonic preparation is prepared using the inventionStock Delivery System (SDS) to which pregnenolone acetate (PA) (3 mg/cc)is added:

Compound Function Amount SDS + PA Primary Delivery System 100 cc + 0.3 gDehydroepiandosterone Skin Stabilizer/Active 1.25 g Diosgenin Active 0.1 g Hypericum Tonic 30.0 cc Camomile Extract Tonic 10.0 cc RosemaryExtract Tonic 10.0 cc Rosehip Extract Tonic 10.0 cc Hosetail ExtractTonic 10.0 cc Pregnenolone acetate Tonic 100 mg

EXAMPLE 5

A tonic formulation, suitable for an over-the-counter hormonal productis produced with the following ingredients:

Compound Function Amount (grams) SDS with Primary Delivery System 100cc  Pregnenolone acetate Active 0.3 (3 mg/cc) Dehydroepiandosterone SkinStabilizer/Active 1.25 Diosgenin Active 0.1 Hypericum Tonic 30 ccCamomile Extract Tonic 10 cc Rosemary Extract Tonic 10 cc RosehipExtract Tonic 10 cc Horsetail Extract Tonic 10 cc Pregnenolone acetateTonic 100 mg

EXAMPLE 6

Another tonic formulation is prepared with the following ingredients:

Compound Function Amount SDS Primary Delivery System 200 cc HypericumTonic 20.0 cc Glycyrrhiza Tonic 20.0 cc NADH Tonic 6.0 mg Dopamine Tonic1.0 mg Diosgenin Active 400 mg Pregnenolone acetate Tonic 50 mg CamomileExtract Tonic 5.0 cc Rosemary Extract Tonic 1.0 cc Rosehip Extract Tonic1.0 cc

EXAMPLE 7

The following hormone therapy formulation, designed for female hormonereplacement therapy, is prepared:

Compound Function Amount SDS+ Primary Delivery 100 cc Ferulic Acid+Complexer 2.0 g Estriol Active 0.6 g Dehydroepi-andosterone SkinStabilizer/Active 4.0 g Progesterone Tonic 4.0 g Pregnenolone AcetateTonic 0.6 g Testosterone Tonic 5.0 g R hormones, e.g., TriestrogensTherapeutic elementper per R

In the above formulation 0.5 grams of pregnenolone may be used in placeof the 0.6 g of pregnenolone acetate.

EXAMPLE 8

This example shows the preparation of an aqueous emulsion topicaldelivery system (OTC) according to the invention for the topicaladministration of the antibacterial Quaternium 28 (dimethyl benzethoniumchloride):

Compound Function Amount (wt. %) Quaternium28 Active 0.25 Adogen ® DHT¹Solvent Modifier 4.0 Lauricidin ® Skin desensitizer; 6.0anti-inflammatory Methylsulfonylmethane Solvent Modifier 2.4 AscorbylPalmitate Solute Modifier 0.3 Vitamin E Acetate Solvent Modifier 0.4Lemon Oil (Cold pressed, highest food grade) Solvent Modifier 0.8D-Panethenol Solvent Modifier 0.1 Allantoin Skin Stabilizer 0.3 Emu OilNatural Oil 1.0 Cetyl Palmitate Skin Stabilizer 0.25 Varisoft ® 475Solvent Modifier 4.0 Decanoic Acid Triglyceride Solvent Modifier 0.3Water (DI) Solvent 79.9

The above ingredients are formulated into an emulsion in which theVarisoft, Adogen, Methylsulfonylmethane and Quaternium compounds arepresent in the aqueous phase; and Lauricidin, Ascorbyl palmitate, Ceylpalpitate, Vitamin E acetate, D-panthenol, allantoin, Emu Oil anddecanoic acid triglyceride are present in the organic phase. The lemonoil is present at the interfaces of the oily and aqueous phases.

¹dihydrogenated tallow dimethyl ammonium chloride; may also function asactive ingredient, e,g., as a pain reliever, and also as ananti-irritant

The formulation may be prepared, for example, by combining the watersoluble ingredients and heating to about 60° C. Separately, the organicphase ingredients are combined and heated to about 63° C. with carebeing taken to avoid temperatures about 70° C., preferably, notexceeding about 65° C. Thereafter, the above water soluble and oilsoluble components are combined by adding the oil phase to the waterphase and mixed in a closed, heated vessel. Water is added to achieve aworkable consistency at which time mixing is continued with addition ofthe remaining water and after cooling to about 50° C. the lemon oil isadded. Mixing is continued for about 1 hour at high, e.g., 1,200 rpm,speed, while continuing to cool. The vessel should, preferably, remainin the closed condition during this cooling. The cooling is convenientlyaccomplished using a cooling jacket on the outside of the mixing vessel.When the mixture cools to about 35° C. it is ready to be transferred tosmaller containers for subsequent handling or transfer.

The mixture becomes quite viscous below about 50° C. so appropriatetransfer procedures should be adopted.

For best results, during the mixing steps, the contents in the mixingvessel should be maintained at a level such that the depth of any vortexformed during mixing is about 25% of the depth in the vessel. Asexpected, the vortex depth will tend to increase as the temperaturedecreases and thickening increases. The mixing should be accomplishedunder conditions which avoid aeration.

EXAMPLE 9

This example describes the results of an animal (mouse) study performedat St. Bartholomew's and The Royal London School of Medicine andDentistry, Department of Experimental Pathology, to establish theefficacy of the topical delivery system, based on the Stock DeliverySystem of this invention for transdermal delivery of Cystamine(2,2′-dithiobisethanamine). A Murine Chronic Granulomatous Air-PouchModel was used for evaluation of the delivery of the drug with SDSversus a control vehicle alone; control vehicle plus drug; and SDSalone.

The Air-Pouch Model was selected as an attractive method for studyinginflammatory processes since rodent air pouch has been shown to developinto a structure resembling the synovium of diarthrodial joints and inview of ease of induction and possibilities or serial sampling of fluidand tissue. In addition, the air pouch has been developed further inmice for use in the examination of the angiogenic response. The murinechronic granulomatous air pouch is advantageous for study in view of theease of therapeutic manipulation in this species used and, further, thedevelopment of the vasculature may be readily assessed by dyeincorporation assays. The metabolic responses of the lining cells of themurine air pouch was assessed for comparison to the enzyme inductionseen in rheumatoid synoviocytes, and the model subsequently used forassessing the potential of varying agents to modulate the angiogenicresponse.

In this study, 1 milligram (mg) of cystamine was added to 0.5 cc ofStandard Stock Solution (SDS) as previously described, or to a controlvehicle (aqueous isopropanol). In each case, the active ingredient(cystamine) was administered in an amount of 30 mg per kilogram of bodyweight.

Mice (TO or BALB/c, for hormone studies, 30±5 g) were lightlyanaesthetized with halothane. Three milliliters of air were injectedsubcutaneously into the scruff of the neck using a 25G needle. The shapeof the air pouch was controlled by manipulation during inflation. Oneday later, 0.5 ml Freund's complete adjuvant supplemented with 0.1%croton oil was injected into the air pouch using a 21G needle. Animalswere killed at various time points for assessment of pouch vascularity,histology and cleared air pouch preparations. Vascularity was assessedby a modified form (see Kimuar et al, [need citation]1986) of theCarmine Red Vascular Casting technique. Mice were anesthetized usinghypnorm/hypnovel and kept warm on a heated box at 40° C. for 10 minutes.One millitier (1 ml) of 25% carmine red dye in 10% gelatin at 40° C. wasinjected into the tail vein of each mouse. Cadavers were chilled at 4°C. for 4 hours and the granulomas dissected free. Granulomas wereweighted after drying in an oven for 2 days at 56° C. The driedgranulomas were digested for 24 hours at 56° C. in 0.9 ml of digestivesolution (12 units ml-¹ papain in 0.05M phosphate buffer, pH 7.0,supplemented with 0.33 g/liter N-acetyl cysteine) for cotton-wrappedcartilage granulomas and 9 ml for air pouch granulomas. A volume of 0.1ml or 1 mol of 4M sodium hydroxide (for each type of granuloma,respectively) was mixed well with each digest. The digests werecentrifuged at 200g for 10 minutes and filtered through a 0.22 μmnitrocellulose disposable filter. The dry content was measuredspectrophotometrically at 490 nm against a standard curve of dye from1-100 μg/ml. Digests were diluted as appropriate to bring them onto thestandard curve and blanked against non-injected control granulomastreated in the same way.

Results are expressed, below, as μg carmine red dye per mg dry tissuemass. In some cases, exudate was recovered from the air pouches attermination, 5M sodium hydroxide added to give a final concentration of0.5M sodium hydroxide and processed as above to determine carminecontent.

Delivery System Dry Weight of Granuloma (mg) Control vehicle (CV) 0.114± 0.113 CV + cystamine 0.115 ± 0.008 SDS 0.1334 ± 0.009  SDS + cystamine 0.082 ± 0.006* *p = 0.291 SDS/(SDS + cystamine) **p = 0.0003

From the above results, namely, a decrease in dry weight of thegranuloma, it is apparent that the SDS is highly effective as a deliveryvehicle which, in fact, converts the normally sub-effective dose (30ms/kg) of cystamine to an effectively dose.

EXAMPLE 10

This example is for an aqueous based weight reducing formula in whichcaffeine and the conjugated isomer of lineolic acid (CLA) are used asthe primary active agents.

The formulation was prepared without use of modeling software.

Amount Ingredient Function (parts by weight) Caffeine Active 0.05 CLAActive 1.2 Aescin Solute Modifier 0.1 Pyridoxal-5- Active/Vitamin 0.001Phosphate (P-5-P) Liquorice Active Hormone 0.05 (20% glycyrrhizic Acid)Modulator Ephedrine Solute Modifier 0.5 Active/CNS StimulantTheophilline Solute Modifier + 1.5 Active/CNS Stimulant Olive OilSolvent Modifier 4.0 Carnitine Solute Modifier 0.1 MSM Solvent Modifier2.0 Ascorbic Palmitate Solvent Modifier 0.15 Lemon Oil Solvent Modifier0.8 Alpha-lipoid acid Solute Modifier 0.2 Lauricidin Skin Stabilizer 1.0Adogen DHT Solvent Modifier 4.65 Allantoin Skin Stabilizer 0.3 Vitamin Eacetate Skin Stabilizer 0.25 Dexpathenol Solvent Modifier 2.0 WaterPrimary Solvent

The above formulation is designed for patients with severe chronicobesity with cardiac complications. Therefore, forskolin is not includedin the formula in view of its cardiotonic effects which, although onlyshort-lived, is considered to present an unnecessary risk. However,under appropriate circumstances forskolin or equivalent may be added tothe formulation with expected improvement in speed of absorption andtotal uptake. In addition, by more closely balancing moles-van der Waalsforces to within about 15% or less further improvements in thepenetration and performance characteristics would be achieved.

EXAMPLE 11

This example is for a pain treating composition, formulated as anointment.

Ingredient Amount (parts by weight) Merguard 0.125 Verisoft 475 3.6Adogen DHT 3.2 Lauricidin 6.0 MSM 2.4 Ascorbic Palmitate 0.3 Vitamin EAcetate 0.4 Lemon Oil 0.8 Dexpanathenol 0.1 Allantoin 0.7 Olive Oil 1.0Cetyl Palmitate 0.25 Dimethyl Benezethonium 0.25 Chloride Decanoic Acid0.7 Triglyceride Sorbitan Palmitate 0.7 Water 5.225

The sum of the total system moles-van der Waals forces is 0.598 whilefor the total system less active agent (Varisoft 475) sum of themoles-van der Waals forces is 0.516.

EXAMPLE 12

The following composition is an aqueous cream formulation designed forpromoting cellulite removal.

Ingredient Amount (parts by weight) CLA 0.3 Aescin 0.1 P-5-P 0.001Liquorice (20%) 0.05 Ephedrine 0.5 Theophilline 1.5 Olive Oil 2.0Carnitine 0.3 MSM 2.0 Ascorbic Palmitate 0.015 Lemon Oil 0.8 Alphalipoid acid 0.2 Lauricidin 2.0 Adogen DHT 2.0 Allantoin 0.3 Vitamin Eacetate 0.25 Dexpanthenol 2.0 Propylene Glycol 2.0 Water

The difference between the moles-van der Waals forces of thecarrier/solvent system (0.506) and the total system (carrier/solventplus active ingredient-therophilline) (0.552) is about 8.33%.

EXAMPLE 13

This example describes the results of an in vitro trial based on thestock delivery system of this invention, for transdermal delivery ofmorphine (as morphine sulfate), in a Franz Diffusion Cell model.

Evaluation of Morphine Formulation

This morphine formulation is designed as a therapeutical product forcancer pain relief.

Presently, transdermal formulations developed for the purpose of cancerpain relief have not yet been found to be successful for practical use.One reason, is that the level of morphine required to show an analgesiceffect is very high, in the order of 70 mg/day (in the case of applyingto a 100 cm² area, a transdermal absorption rate of 27 μg/hr/cm₂ isnecessary) if an absorption enhancer strong enough to have such a highlevel of morphine absorbed transdermally is used, it is inevitable thatserious skin irritation will result.

The evaluation of the subject formulation was performed in vitro withskin taken from a hairless rat. Since the barrier ability of the stratumcorneum does not differ between in vitro and in vitvo status,transdermal absorption may be correlated evaluated with the in vitroskin permeation test.

Experiment

2 kinds of SDS vehicles were used:

SDS-L for topical use—lotion (see Table 8);

SDS-S for systemic use—lotion (see Table 9).

The morphine sulfate was supplied by Sankyo Pharmaceuticals, Japan.

TABLE 8 Compound Mole Wt. Amt (g)/100 ml Morphine Sulfate 668.77 0.25SDS-L MSM 94.13 2 Ethanol 46.07 56.881 Water 18 2.862 Propylene Glycol76.01 42.131 Limonene 136.24 0.102 Vit E 430.17 0.051 Dexpanthenol205.25 0.053 MSM 94.13 0.102 Lauriciden 181.97 0.254 Oxindole 2.95 0.003Thioproprionic Acid 178.21 0.051 Forskolin 4.10 0.010

TABLE 9 Compound Mole Wt. Amt (g)/100 ml Morphine Sulphate 668.77 0.25SDS-S Ethanol 46.07 57.243 Acetone 58.08 5.0 Propylene Glycol 76.0142.131 Limonene 136.24 0.102 Vit E 430.17 0.051 Dexpanthenol 205.250.053 MSM 94.13 0.102 Lauriciden 181.97 0.254 Oxindole 295 0.003Thioproprionic acid 178.21 0.051 Forskolin 4.10 0.010 BalancingComponents ATP 507.17 0.25 Limonene 136.24 1.0 DMAE 89.14 1.0 BenzylAlcohol 108.44 0.5 MSM 94.13 3.0

The standard stock solution, SDS-L, is not optimized for systemperfusion. However, for the systemic stock solution, SDS-S, theadditional MSM, additional limonene, DMAE and benzyl alcohol are addedto the solution to balance the formula as previously described. Thus,the sum of the products van der Waals-moles for the ingredients of SDS-S(namely, ethanol, acetone, propylene glycol, Vitamin E, dexpanthenol,methylsulfonylmethane (MSM), lauriciden, oxindole, thioproprionic acid,and Forskolin) is a 4.742, whereas the sum of the products VDW-moles forthe final formula (including morphine sulfate, additional MSM,additional limonene, dimethylaminoethanol (DMAE), and benzyl alcohol) isa 4.861, a difference of only about 2.44%; additional limonene,dimethylaminoethanol (DMAE), and benzyl alcohol) is 4.861, a differenceof only about 2.44%.

Skin Permeation Test

A vertical standing static type Franz Cell is employed. The receptorphase is maintained at 37° C. by circulating uniformly heated water.

Skin is taken from the abdomen of a hairless rat, male, 12 weeks of age,purchased from Charles River Laboratories, and the skin is stored fortwo weeks at −60°. Just before use the skin is gently thawed to roomtemperature and then cut into circular shapes with a diameter of 3.5 cmand set into the Franz Cell device.

The topical and systemic preparations are prepared by adding 28 mg ofmorphine sulfate to 10 ml each of SDS-L and SDS-S while stirring at roomtemperature until the morphine sulfate is completely dissolved andallowing the mixture to stand overnight, while tightly sealed.

In order to compare effectiveness of the formulations as a lotion and asa patch, the evaluations are made on two kinds of applications: opencondition, which mimics the application of a lotion formulation and,closed condition, which mimics the application of a patch formulation,as follows:

(i) Open Condition

At the beginning of the skin permeation test, 1 ml of the morphinesulfate combined with SDS-L or morphine sulfate combined with SDS-S isplaced in the Donor Chamber of the Franz Cell. Air is introduced for 10minutes by a drier to volatilize the volatile components in the vehicle.The Donor chamber is kept open until the completion of the test.

(ii) Closed Condition

At the beginning of the skin permeation test, 1 ml each of the morphinesulfate combined with SDS-L or morphine sulfate combined with SDS-S isplaced in the Donor chamber of the Franz Cell. The Donor chamber is keptcompletely sealed until the completion of the test.

Isontonic phosphate buffer, pH 7.2, consisting of 0.033 mM sodiumphosphate, 7.4% NaCl and 1% NaN₃, (preservative) is used as the receptorsolution.

At each sampling time, established beforehand, 1.8 ml of the solution inthe receptor chamber is sampled, and the same volume of receptorsolution is added to the receptor chamber.

The concentration of morphine sulfate in each receptor solution sampledis determined quantitatively by HPLC.

Based on the morphine sulfate concentration in the receptor solutionobtained as above, the amount of morphine sulfate permeated per 1 cm² ofskin is cumulatively calculated, then plotted against each samplingtime. On the resulting skin permeation profiles, the region where thereis a linear relation between the permeated morphine sulfateconcentrations and the sampling times is chosen. Then the linearequation that best fit the region is determined by the least squaresmethod. The “permeation flux” is obtained from the slope and the “lagtime” from the time-axis intercept. The tests are repeated three timesand the average and standard deviation (SD) of the “permeation flux” andthe “lag time” are calculated.

Results

1. pH Values or Morphine Sulfate Combined with SDS-L and MorphineSulfate Combined with SDS-S

The pH values of vehicle combined with morphine sulfate (at 2.6 mgmorphine sulfate/ml) was 6.14 for SDS-L and 5.77 for SDS-S,respectively. Both formulations are non-toxic to the skin.

2. Volatility of Solvent under Open Conditions

Approximately half the volume of the solvent remained (not volatized)after ventilation for 10 minutes with the drier. After extending thetest for 29 hours, about {fraction (1/10)} volume of the solvent stillremained in the donor cell.

3. Skin permeation of the Morphine Sulfate from the Stock Solution

Tables 10 and 13 and FIGS. 1-4 show the cumulative permeated amount ofmorphine sulfate per 1 cm² of hairless rat skin over time. Table 14shows the permeation of flux and lag time of morphine sulfate obtainedfrom the permeation profiles in FIG. 1. For both SDS-L and SDS-Smorphine sulfate is detected in the receptor solution after 6 hours.Thereafter, the permeation flux is approximately twice as fast in SDS-Sthan in SDS-L. In the case of SDS-L, there is little or no difference inthe permeation flux or the lag time between the open conditions and theclosed conditions. In the case of SDS-S, there is also little or nodifference in the flux or lag time between open and closed conditions.

TABLE 10 Amount of morphine sulfate through 1 cm² of hairless rat skinfrom SDS-L (open condition) Amount of morphine sulfate through 1 cm² ofhairless rat skin (ug/cm²) Time (hr) s-1 s-2 s-3 mean sd¹) 0 0 0 0 0 0 30 0 0 0 0 6 0 0 0 0 0 22 118 6 8 44 64 26 373 44 48 155 189 29 564 141119 275 251 ¹)standard deviation

TABLE 11 Amount of morphine sulfate through 1 cm² of hairless rat skinfrom SDS-L (closed condition) Amount of morphine sulfate through 1 cm²of hairless rat skin (ug/cm²) Time (hr) s-1 s-2 s-3 mean sd¹) 0 0 0 0 00 3 0 0 0 0 0 6 0 0 0 0 0 22 6 22 7 12 9 26 40 179 158 126 75 29 158 327324 270 97 ¹)standard deviation

TABLE 12 Amount of morphine sulfate through 1 cm² of hairless rat skinfrom SDS-S (open condition) Amount of morphine sulfate through 1 cm² ofhairless rat skin (ug/cm²) Time (hr) s-1 s-2 s-3 mean sd¹) 0 0 0 0 0 0 30 0 0 0 0 6 0 0 0 0 0 22 67 865 125 352 445 26 290 1140 447 626 452 29464 1263 694 807 412 ¹)standard deviation

TABLE 13 Amount of morphine sulfate through 1 cm² of hairless rat skinfrom SDS-S (closed condition) Amount of morphine sulfate through 1 cm²of hairless rat skin (ug/cm²) Time (hr) s-1 s-2 s-3 mean sd¹) 0 0 0 0 00 3 0 0 0 0 0 6 0 0 0 0 0 22 717 599 1091 802 257 26 1040 940 1256 1079162 29 1256 1112 1375 1248 132 ¹)standard deviation

TABLE 14 Permeation flux and lag time of morphine sulphate from SDS-L orSDS-S through hairless rat skin formulation application methodflux(g/hr/cm²) lag time (hr) MS-1 open 33± 21 ± 1 closed 36± 22 ± 0 MS-2open 65± 16 ± 8 closed 64±  7 ± 10

EXAMPLE 14

This example describes the result of an animal (hairless rat) studyperformed to further establish the efficacy of the topical deliverysystem, based on the stock delivery system of this invention fortransdermal delivery of morphine (mol. Wt. 285.34) and also foracyclovir (mol. Wt. 225.21) and testosterone (mol. Wt. 288.43). Theacyclovir and testosterone formulations are shown in Tables 15 and 16,respectively. The morphine formulation is shown in Table 9 above. Apilot trial is performed on three hairless rats, during which a baselineblood sample is drawn, then 1 ml of the topical delivery systemcontaining a titrated dose of each of the three test drugs isadministered to each of the rats. Sample are harvested at 30 and 60minutes. The results are as follows:

Medicament Dose in 1 ml Baseline 30 minutes 60 minutes Morphine 2.5 mg 0Ins. Sample 45 nmol/L Testosterone   5 mg 165 1,552 ng/dl 1600/dlAcyclovir 0

In view of these encouraging results a full-scale protocol trial isperformed on 15 hairless rats, divided into three groups of five ratseach. One group is dosed with the morphine formulation of Table 10, onewith the testosterone formulation of Table 11 and one with the acylovirformulation of Table 12. Samples for the morphine and acyclovir groupsare taken at 30 minutes, 60 minutes and 120 minutes. Samples from thetestosterone group are taken at Baseline −0 minutes, 30 minutes and 60minutes. The results are as follows:

Medicament Dose in 1 ml Baseline 30 minutes 60 minutes Morphine 2.5 mg 0nmol/L nmol/L Acyclovir 0 ng/dl ng/dl Testosterone   5 mg 165 ng/dlng/dl

Testosterone levels are increased 10-fold in one hour. A 2.5 mg dose ofmorphine, a dose which would be considered insufficient to accomplish atherapeutic outcome if dosed intravenously, provides blood levelsequivalent to a 10 mg IV dose. Further, morphine is considered extremelydifficult to deliver transdermally due to its highly lipophiliccharacter.

The kinetic outcomes for all three molecules would be sufficient toaccomplish therapeutic doses in human beings.

TABLE 15 Acyclovir Formulation Compound Mole Wt. Amt/100 ml Acyclovir225.09 MSM 94.13 3 5 SDS VitE 430.17 0.051 Despanthenol 205.25 0.053 MSM94.13 0.10 Lauriciden 181.97 0.25 Oxindole 295 0.003 Forskoline 4100.010

The sum of moles-van der Waals forces for the SDS components is 0.0252while the sum of moles-van der Waals forces for the SDS plus acyclovirand additional MSM is 0.0353.

TABLE 16 Testosterone Formulation Compound Mole Wt. Amt./100 mlTestosterone 288.4 5.0 Ethanol 46.07 54.381 Water 18 2.862 PropyleneGlycol 76.01 42.131 limonene 136.24 0.102 VitE 430.17 0.051 Dexpanthenol205.25 0.053 MSM 94.13 0.102 Lauriciden 181.97 0.254 Oxindole alkaloid295 0.003 Forskolin 410 0.010

In order to determine the transdermal absorption of testosterone fromthis formulation, the formulation is applied to rat skin (n=6) and theamount of absorbed through the skin is measured at 0, 30 and 60 minutes.The results obtained are shown in the following Table 17.

TABLE 17 Testosterone absorption though the skin Plasma testosterone,ng/gl Time Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean Median 0 171 50 211229 366 165 199 191 30 815 152 668 893 1577 1552 943 854 60 542 222 5531321 2137 >1600 1062 937

EXAMPLE 15

The following lotion for transdermal delivery of male hormones isprepared.

Compound Mole Wt. Amt/100 ml DHEA 288.4 1231 Diosgenin 414.6 0.115Androstenedione 286.4 3.007 Ethanol 46.07 70.0 Acetone 58.08 Water 182.95 Propylene Glycol 76.01 22.0 limonene 136.24 0.10 VitE 430.17 0.06Dexpanthenol 205.25 0.06 MSM 94.13 2.0 Lauriciden 181.97 0.20 Oxindole295 0.01 Thioproprionic acid 178.21 Forskolin 4.10 0.04 Indole3-Carbinol Rosemary

EXAMPLE 16

This example is directed to a formulation for transdermal delivery ofhuman growth hormone (HGH) (MW=20,000) using modified form of thestandard stock delivery system according to this invention:

Amt/100 ml HGH 0.20 Cyclodextrin 5.0 MSM 1.5 Vitamin E 0.1 Dexpanthenol0.055 Phytantriol 0.025 Oxindole 0.15 Forskolin 0.50 Tween 80 0.924Ceterath 20 1.5 Guaifenensin 0.6 Inositol 0.6 Propylene Glycol 100.0Water 10.0

EXAMPLE 17

This example illustrates modification of the proportions of the activeingredients and delivery system to match the physicochemical properties(here, van der Waals forces) of the active ingredients and carriersystems, to maximize effectiveness of the transdermal delivery of theactive ingredients. In this case, the active ingredients, including thecombination of Lorazepam and Ibuprofen, provide an anxiolytic or musclerelaxant treatment.

Formula 17-A Formula 17-B Ingredient Amt/100 ml Amt/100 ml Flubiprofen 1.0 0 0.75 Diazepam 0.5  0.5 Ibuprofen 0.8  0.8 Lorazepam 0.3  0.3 MSM4.0  4.0 Ethanol 56.9  56.9 Water 18.0  18.0 Propylene Glycol 42.1  42.1Limonene 0.10 0.10 Vitamin E 0.05 0.05 Dexpanthenol 0.05 0.05 MSM 0.100.10 Lauriciden 0.25 0.25 Oxindole  0.003 0.003 Thioproprionic Acid 0.050.05 Forskolin 0.01 0.01 Vinpocetine 0.01 0.01 Resveratrol 0.02 0.02Emodin 0.01 0.01 Cyclobenzaprin HCl 0.50 0.80 Inositol 0.60 0.60Guaifenensin 0.60 0.60 Prozac 1.0  0.5 GABA 1.0  1.0

For formula 17-A the sum of the moles-van der Waals (VDW) for deliverysystem is 2.892 while for the delivery system and activities, the sum is5.021. However, for formula 17-B the sum of moles-VDW is 2.838 fordelivery system and 2.9687 for delivery system plus actives.

REFERENCES

1. T. K. Ghosh, et al., Methods of Enchancement of Transdermal DrugDelivery, Parts I, IIa*IIb, Chemical Permeation Enhancers, Pharm, Tech.17 (3): 72-98m 17 (4): 62-89m 17 (5): 68-76 (1993).

2. Crouch, James E., Functional Human Anatomy, Lea & Fibiger, LOCCN65-12968, Chapter 6, pp. 88-97, 1965.

3. K. Tojo, Random Brick Model for Drug Transport Across StratumCorneum, J. Pharm, Sci., 76:889-891

4. S. D. Roy, Preformulation Aspects of Transdermal Delivery Systems,In: Transdermal and Topical Drug Delivery Systems, Eds. T. K. Ghosh, W.R. Pfister, S. I. Yum, Interpharm Press, Inc., Buffalo Grove, Ill. 1997.

5. K. Gjesdal, et al., Transdermal Nitrate Therapy: BioavailabilityDuring Exercise Increase Transiently after the Daily Change of thePatch, Brit. J. Clin. Pharmacol. 31:560-562 (1991).

6. K. Tojo, The Predication of Transdermal Permeation: MathematicalModels, In: Transdermal and Topical Drug Delivery Systems, Eds., T. K.Ghosh, et al., Interpharm Press, Buffalo Grove, Ill., 1997.

7. I. Diez, et al., A Comparative In Vitro Study of TransdermalAbsorption of a series of Calcium Antagonist, J. Pharm. Sci. 80:931-934(1991)

8. W. R. Pfister, et al., Permeation Enhancer Compatible withTransdermal Drug Deliery Systems, Parts I & II: Selection andFormulation Considerations, Pharm. Tech. 14(9):132-140, 14 (10):56-60.

9. C. D. Vaughn, Using Solubility Parameters in Cosmetic Formulations,J. Soc. Cosmet. Chem. 36:319-333 (1985).

10. J. W. Streilein, In: Immune Mechanisms in Cutaneous Diseases, Ed. D.A. Norris, Marcel Dekker, Inc., New York, pp. 73-96 (1989).

11. J. Ademola, et al., Safety Assessment of Transdermal and TopicalDermatological Products In: Transdermal and Topical Drug DeliverySystems, Eds. T. K. Ghosh, et al., Interpharm Press, Inc., BuffaloGrove, Ill., (1997).

12. P. Liu, et al., Quantitiative Evaluation of Ethanol Effects onDiffision and Metabolism of β-Estradiol in Hairless Mouse Skin, Pharm.Res. 8:865-872 (1991).

13. Lubert Styer, Biochemistry, 2^(nd) Edition, Chapter 35, pp. 839-858,W. H. Freeman, CO., New York, (1981).

14. Kenneth B. Seamon, et al., Foskolin: Unique Diterpene Activator ofAdenylate Cyclase in Membranes and Intact Cells; PNAS, vol. 78, no. 6,pp. 3363-3367 (June 1981).

15. Hermann P. T. Ammon, et al., Forskolin: From Ayurvedic Remedy to aModer Agent; Planta Medica, pp. 473-476 (1985).

What is claimed is:
 1. A method of making a transdermal delivery system(TDS) comprising the steps of: (a) selecting one or more active agent;(b) determining a transdermal effective dose of said active agent, saideffective dose of said active agent having molecular propertiesincluding van der Waals forces and dipole moments; (c) quantifying saiddipole moments of said effective dose of active agent; (d) determiningan amount of a solvent to solubilize said effective dose of said activeagent, said amount of said solvent having molecular properties includingvan der Waals forces and dipole moments; (e) quantifying said dipolemoments of said amount of said solvent to solubilize said effectivedose; (f) comparing said of dipole moments of said effective dose saidactive agent and said dipole moments of said solvent; (g) determiningthat said dipole moments of said solvent are substantially the same assaid dipole moments of said active agent and said solvent; (h) combiningsaid solvent and said motive agent forming a true solution of saidsolvent and a solute.
 2. A method of making a TDS of claim 1 furthercomprising (a) selecting additional ingredients for said TDS forming asolvent system, said additional ingredients including at least one ofsolute modifiers, solvent modifiers, compositions for release ofcellular energy, skin stabilizers, membrane permeability modifiers,capillary dilators and combinations thereof, each of said additionalingredients having molecular properties including van der Waals forcesand dipole moments; (b) quantifying said dipole moments of each of saidadditional ingredients and determining that said dipole moments of saidsolvent system are substantially the same as said molecular propertiesof said solvent system and said active agent; (c) combining said solventsystem and said active agent.
 3. A method of making a TDS of claim 1further comprising (a) quantifying the mol-amounts of said active agentconstituting a transdermal effective dose; (b) quantifying themol-amounts of said solvent to solubilize said mol-amounts of saidactive agent; (c) determining the dipole moments of said mol-amounts ofsaid active agent; (d) determining the dipole moments of saidmol-amounts of said solvent; (e) calculating a weighted average of saiddipole moments of said mol-amounts of said active agent and saidmol-amounts of said solvent; (f) adjusting said solvent mol-amounts anddipole moments to more closely match said dipole moments of said activeagent; and (g) combining said mol-amounts of said active agent and saidmol-amounts of said solvent to arrive at a combination having totaldipole moments approximating said dipole moments of said solvent.
 4. Amethod of making a TDS of claim 2 further comprising (a) quantifying themol-amounts of said active agent constituting an effective dose; (b)quantifying the mol-amounts of said solvent to solubilize saidmol-amounts of said active agent; (c) quantifying the mol-amounts ofsaid additional ingredients to affect transdermal migration; (c)determining the dipole moments of said mol-amounts of said active agent;(d) determining the dipole moments of said mol-amounts of said solvent;(e) determining the dipole moments of the mol-amounts of each of saidadditional ingredients; (f) calculating a weighted average of saiddipole moments of said mol-amounts of said active agent and saidmol-amounts of said solvent system; (g) summing the total dipole momentsof said mol-amounts of active agent and said solvent system; (h)combining said mol-amounts of said additional ingredients, saidmol-amounts of said solvent, and said mol-amounts of said active agentto arrive at a combination having total dipole moments approximatingsaid dipole moments of said active agent.